The role of mannose-binding lectin (MBL) in diabetic retinopathy: A scoping review.

Diabetes mellitus (DM) is a chronic systemic disease characterized by a multifactorial nature, which may lead to several macro and microvascular complications. Diabetic retinopathy (DR) is one of the most severe microvascular complications of DM, which can result in permanent blindness. The mechanisms involved in the pathogenesis of DR are multiple and still poorly understood. Factors such as dysregulation of vascular regeneration, oxidative and hyperosmolar stress in addition to inflammatory processes have been associated with the pathogenesis of DR. Furthermore, compelling evidence shows that components of the immune system, including the complement system, play a relevant role in the development of the disease. Studies suggest that high concentrations of mannose-binding lectin (MBL), an essential component of the complement lectin pathway, may contribute to the development of DR in patients with DM. This review provides an update on the possible role of the complement system, specifically the lectin pathway, in the pathogenesis of DR and discusses the potential of MBL as a non-invasive biomarker for both, the presence and severity of DR, in addition to its potential as a therapeutic target for intervention strategies.

Mannose Binding Lectin and C3 Serum Levels in Coronary Artery Disease: A Cross-Sectional Study.

BACKGROUND: The process of tissue injury in coronary artery disease (CAD) has been associated with activation of the complement system, partly due to the action of mannose-binding lectin (MBL) and C3, which are expressed in atherosclerotic lesions. OBJECTIVE: The aim of this study was to evaluate the serum levels of MBL and C3 in patients with CAD and to compare them with healthy controls. Additionally, we aim to assess the correlation between MBL and C3 levels and cardiometabolic parameters. METHODS: MBL and C3 serum concentration were determined by ELISA and immunoturbidimetry, respectively, in up to 119 patients undergoing coronary angiography for CAD evaluation, comprising 48 individuals diagnosed with acute myocardial infarction (MI) and 71 without MI. A total of 93 paired healthy controls were included in the study. RESULTS: Individuals with CAD had MBL serum concentration higher than controls (p = .002), regardless of the presence of MI (p = .006). In addition, high concentration of MBL (>2000 ng/mL) was more frequent in patients with CAD (p = .007; OR = 2.6; 95% CI = 1.3-5.1). C3 levels were not significantly associated with any of the patient groups but were positively correlated with cardiometabolic parameters such as body mass index (BMI) and triglycerides levels. CONCLUSIONS: Higher concentrations of MBL were found to be associated with CAD, whereas C3 levels were found to be associated with cardiovascular risk factors.

Association of neutrophil extracellular trap levels with Raynaud's phenomenon, glomerulonephritis and disease index score in SLE patients from Brazil.

Neutrophil extracellular traps (NETs) are cell-extruded DNA strands coated with neutrophils' nuclear proteins and enzymes from cytotoxic granules, produced by NETosis, a cell death pathway. They perform an important defensive role in innate immunity, but their increased production and/or inefficient degradation expose new antigens, such as DNA or citrullinated histone peptides, triggering autoimmunity. This study aimed to access possible associations between serum NETs levels with epidemiological, clinical, and serological data from a well-characterized SLE Brazilian patients' cohort. NET levels were evaluated in one hundred seventy serum samples of patients with Systemic Lupus Erythematosus (SLE) using an Immunoassay. Univariate and multivariate binary logistic regression used clinical patients' data as independent variables. Parametric and non-parametric tests compared log10 base serum NET levels transformed between patients' groups. SLE patients were also dichotomized into "High serum NET levels" and "Low serum NET levels" groups. All analyses were performed in R language 4.1.2, and p < 0.05 were considered significant. Increased susceptibility for high serum NET levels was observed in SLE patients with Raynaud's phenomenon (OR = 2.30, 95 % CI = 1.06-5.21 and p = 0.039), independently of any other risk factor. Also, SLE patients with Raynaud's phenomenon presented higher mean NET serum levels (mean = -0.13 vs. -0.51, p = 0.01). In addition, higher mean NET serum levels were associated with glomerulonephritis (mean = -0.45 vs. -0.12, p = 0.03). Ultimately, the SLEDAI index scored higher in the high NETs serum levels group (median = 2.0 vs. 0.0, p = 6 × 10-3). The formation of NETs might be implicated in Raynaud's phenomenon, glomerulonephritis, and disease index score in SLE patients. Our results highlight the importance of serum NET levels as a possible therapeutical target to modulate the clinical course of SLE.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Intestinal histological findings in patients with spondyloarthritis: a study of the relationship with disease activity.

The role of intestinal microbioma and subclinical bowel inflammation in the etiology of sponsyloarthritis (SpA) has gained a lot of attention recently. Almost 65% of SpA patients will have asymptomatic bowel inflammation if assessed by ileocolonoscopy. The connection between intestinal inflammation and SpA originated the gut-joint axis hypothesis in which monocytes and T cells found in the joint would have origin in the gut.

Intestinal histological findings in patients with spondyloarthritis: a study of the relationship with disease activity

The role of intestinal microbioma and subclinical bowel inflammation in the etiology of sponsyloarthritis (SpA) has gained a lot of attention recently. Almost 65% of SpA patients will have asymptomatic bowel inflammation if assessed by ileocolonoscopy. The connection between intestinal inflammation and SpA originated the gut-joint axis hypothesis in which monocytes and T cells found in the joint would have origin in the gut (AU)

Cytotoxic and Phytotoxic Activities of Native Brazilian Forest Gabiroba (Campomanesia xanthocarpa Berg.), Fruits, and Flour against Shrimp (Artemia salina L.) and Lettuce (Lactuca sativa L.).

Gabiroba, a native fruit in Brazil's Atlantic Forest region, has significant nutritional and therapeutic properties. However, due to its seasonality, consumption by the population is limited. Thus, the development of gabiroba byproducts would add significant value to the food and therapeutic industries. Therefore, it is essential to study and support the lack of toxicity of gabiroba fruit extracts. In the present study, physicochemical analyses of fresh fruits (GF) and dehydrated whole gabiroba flour (WGF) and preliminary toxicity analyses of WGF were performed. The toxicity results showed a microcrustacean LC50 of >1000 mg/mL when exposed to WGF extracts at various concentrations (10-1000 µg/mL; p = 0.062) using the Artemia salina method, with no evidence observed of proliferative activity or toxic metabolic compounds in the WGF extract. The phytotoxicity of WGF using Lactuca sativa L. allowed germination and root growth at various concentrations of WGF extract, with the lowest (100 µg/mL) and highest (1000 µg/mL) concentrations exhibiting 98.3% and 100% seed germination, respectively. In conclusion, these results indicate that the WGF preparation preserved the nutritional and antioxidant potential of gabiroba fruits and that WGF is safe for use as a raw material in the food industry and for therapeutic purposes.

Phytochemicals and Biological Activities of Burdock (Arctium lappa L.) Extracts: A Review.

Arctium lappa L., also known as burdock, is an edible wild plant which has the ability to grow in distinct environments and is considered a weed in several parts of the world. This species has great value in the biological and medical fields with its major secondary components being phenolic compounds and terpenes, substances rich in desired biological activities as antioxidant, antimicrobial, antitumor and anti-inflammatory. In addition, burdock leaves extracts have shown a modulatory effect on the complement system, which plays an important role in the development of inflammatory diseases, with an inhibitory effect on all complement pathways. Thus, natural products with those relevant activities are promising agents for healthcare applications. Therefore, the species A. lappa may represent an interesting asset for researching and developing new therapies for inflammatory afflictions.

Bioactive Secondary Plant Metabolites from Euphorbia umbellata (PAX) BRUYNS (Euphorbiaceae).

The species Euphorbia umbellata has been used to treat inflammatory diseases, cancer, and ulcers. Biological activities reported in the literature, including antiproliferative, cytotoxic and anti-inflammatory, are attributed to the chemical constituents present in its composition as terpenes and polyphenolic compounds. The most recurrently verified metabolites in the Euphorbiaceae family plant species are terpenes, of which euphol is a major constituent with broadly reported cytotoxic, antinociceptive and anti-inflammatory effects; it frequently appears in various extracts obtained from the plant. Euphol has a documented inhibitory effect on neutrophil chemotaxis and can modulate the complement system. Since complement system activation is intimately intertwined with autoimmune and inflammatory diseases, tumor growth promotion and metastasis, plant metabolites from Euphorbia umbellata might influence the outcomes of inflammatory processes. We believe that this is the first review presenting the current knowledge on Euphorbia umbellata secondary metabolites and their biological activities.

MASP1 Gene Polymorphism and MASP-3 Serum Levels in Patients with Chronic Chagas Disease.

INTRODUCTION: Chagas disease (CD), caused by Trypanosoma cruzi, is a major public health issue worldwide affecting 6-7 million people, mainly in Latin America. The complement system plays a crucial role in host immune defense against T. cruzi infection and during the chronic phase of CD; however, the role of the MBL-associated serine protease 1 (MASP1) gene encoding MASP-1, MASP-3, and MAp44 complement proteins has not yet been reported in CD. This study investigated the possible association between MASP1 gene polymorphisms and MASP-3 protein serum levels in chronic CD and its clinical forms. METHODS: Five polymorphisms of MASP1 gene regulatory regions were genotyped in 214 patients with CD and 197 healthy controls (rs7609662 G>A, rs13064994 C>T, rs72549262 C>G, rs1109452 C>T and rs850314 G>A). MASP-3 serum levels were assessed in 70 patients and 66 healthy controls. Clinical data, serum levels of complement proteins (ficolin-2, ficolin-3 and MBL) and inflammatory markers (pentraxin-3 and hsCRP) were also included in the analyses. RESULTS: A significant association of the MASP1 GC_CCA haplotype with CD (padj= 0.002; OR 3.17 [1.19-8.39]) and chronic chagasic cardiomyopathy (CCC) (padj= 0.013; OR 4.57 [1.37-15.16] was observed. MASP-3 and pentraxin-3 levels were positively correlated in the patients (rho = 0.62; p = 0.0001). MASP-3 levels were not associated with MASP1 polymorphisms or CD and its clinical forms. Furthermore, no correlation was observed between MASP-3 levels and that of ficolin-2, ficolin-3, MBL and hsCRP. CONCLUSION: Our findings suggest a possible role for the MASP1 GC_CCA haplotype in susceptibility to chronic CD and CCC clinical forms.

Effects of okra (Abelmoschus esculentus (L.) Moench) on glycemic markers in animal models of diabetes: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Okra (Abelmoschus esculentus (L.) Moench) is traditionally used by different populations of Africa, América, Asia, and Europa to control diabetes. Although its action has been evaluated in several preclinical rodent trials, they have not been systematically analyzed. OBJECTIVE: To evaluate the effectiveness of using okra in the treatment of diabetes in experimental rodent models. MATERIAL AND METHODS: Controlled and randomized rodent animal trials with induced diabetes published between January 2000 and January 2021 were searched in the PubMed, Scopus, Scielo, and Web of Science databases. The search strategy included studies comprising the descriptors: animal species, diabetes induction method, intervention time, part of okra fruit used (whole, seeds, or peels), and dose as well as observed effects on biochemical and metabolic parameters. The systematic review was carried out according to the PRISMA statement, Cochrane bias risk tool (SYRCLE's RoB tool), and registered for systematic review protocols (PROSPERO). RESULTS: A total of 326 articles were identified and after the exclusion of studies with gestational animal models, non-rodent animals, and non-diabetic animals, 11 studies involving 388 rodents were selected for the synthesis of results. The diabetes induction methods included streptozotocin, streptozotocin-nicotinamide, alloxan monohydrate, insulin resistance by high-fat diets or formulation described in AIN - 76, and feeding with high-fat food. Both Wistar albino rats, Sprague-Dawley males, and rats of both sexes of the Long-Evans lineage as well as male albino mice and C57BL females were included in the experiments. Studies showed that extracts of the fruit, the fresh fruit, or its various fractions had positive effects on the following markers: glycated hemoglobin, cholesterol, HOMA-IR, oral glucose tolerance test, and blood glucose, in acute (2 and 24 h), and chronic (up to 4 months) treatment. CONCLUSION: An important hypoglycemic effect of okra in its various fractions on induced diabetes was observed by different authors. Moreover, okra promoted improvement in metabolic markers such as insulin sensitivity, lipid profile, and bodyweight loss.

Ficolin activation as a potential biomarker of the severity of schizophrenia.

Several studies have examined the complement system in schizophrenia, suggesting an involvement of the lectin pathway. We analyzed 49 patients with schizophrenia and explored the association between psychopathology of schizophrenia and complement component 3 (C3) serum levels, C-reactive protein (CRP) serum levels, ficolin activation, and mannose-binding lectin (MBL) activation. In the multiple regression analysis, a negative association was observed between the Positive and Negative Syndrome Scale (PANSS) total score and ficolin activation. Body mass index (BMI) was positively associated with the serum levels of C3 and CRP. MBL activation was not associated with any independent variables. Our findings facilitate a better understanding of the complement system in schizophrenia. Additional studies with a large sample population are needed to confirm our results.

The lectin pathway of complement and the initial recognition of Leishmania infantum promastigotes.

Visceral leishmaniasis (VL) is a neglected and highly lethal disease. VL is endemic in South American countries, with Brazil being responsible for 96% of the cases. In this continent, VL is caused by the protozoan Leishmania (Leishmania) infantum (L. infantum), transmitted by the bite of infected female phlebotomine sandflies. Immediately after the inoculation of L.infantum promastigotes into the vertebrate host, the complement, as part of the first line of innate response, becomes activated. L. infantum promastigotes glycocalyx is rich in carbohydrates that can activate the lectin pathway of complement system. In this study, we evaluated whether the lectin pathway collectins [manose binding lectin (MBL) and collectin-11 (CL-11)] and ficolins (-1, -2 and -3) interact with L.infantum promastigotes, using confocal microscopy and flow cytometry. The binding of MBL, CL-11 and ficolins -1 and -3, but not ficolin-2, was observed on the surface of live metacyclic promastigotes after incubation with normal human serum (NHS) or recombinant proteins. C3 and C4 deposition as well as complement mediated lyses was also demonstrated after interaction with NHS. These results highlight a role for collectins and ficolins in the initial immune response to L.infantum.

Immunomodulatory and cytotoxic activities of euphol.

AIMS: This study evaluated the effect of euphol isolated from Euphorbia umbellata (Pax) Bruyns latex on the activation of complement pathways (classical (CP), alternative (AP) and lectin (LP)), neutrophil chemotaxis, cytotoxic activity, cell morphology and death in HRT-18 and 3T3 cells lines. MAIN METHODS: CP and AP were assessed using hemolytic assays and ELISA for LP; neutrophil chemotaxis was performed using Boyden's chamber; cytotoxicity was evaluated by neutral red methodology and characteristics of cell death were assessed by cell morphology with hematological staining. KEY FINDINGS: Although euphol increased CP activation (38% at a concentration of 976.1 µM), an inhibitory effect on AP, LP (31% and 32% reduction in the concentration of 976.1 µM) and neutrophil chemotaxis (inhibit 84% of neutrophil migration at a concentration 292.9 µM) was observed. In addiction euphol was able to induce significant cell death in a time-dependent manner, presenting an IC50 of 70.8 µM and 39.2 µM for HRT-18 and 3T3 cell lines respectively and it was also observed apoptotic characteristics as cellular rounding, chromatin condensation and blebs formation for both cell lines. SIGNIFICANCE: Euphol has a potential use for the treatment of complement-related inflammatory diseases due to its ability to downregulate inflammation. On the other hand, the controlled activation of CP can contribute to complement-dependent cytotoxicity in the context of monoclonal antibody-based cancer treatment.

A comparative approach on the activation of the three complement system pathways in different hosts of Visceral Leishmaniasis after stimulation with Leishmania infantum.

Visceral Leishmaniasis is an infectious disease that affects mainly humans and dogs, with the latter being important reservoirs of the parasite. Conversely, cats are naturally resistant. The immune system can offer important explanation to this problematic as there is no evidence on the role that the complement system plays in cats. In this context, effect of the complement system from human, dog and cat sera on Leishmania infantum was evaluated. Activation of the classical, alternative and lectin pathways was assessed through hemolytic and ELISA assays. Lytic activity of the complement on the parasite's viability was investigated by Transmission Electron Microscopy and Flow Cytometry. Complement proteins were more consumed in dog serum on the classical and alternative pathways, leading to less hemolytic activity, and only in cat serum they were consumed on the lectin pathway when incubated with L. infantum. Lytic activity on the parasite's surface was more accentuated in human serum, and varied throughout the parasite's developmental stages.

Impact of VSIG4 gene polymorphisms on susceptibility and functional status of rheumatoid arthritis.

The complement receptor of the immunoglobulin superfamily (CRIg, encoded by the VSIG4 gene) is a macrophage receptor involved in the clearance of immune complexes and autologous cells. Our results suggest that the VSIG4 rs1044165T allele is a risk factor for severe functional status of rheumatoid arthritis in women, possibly by affecting VSIG4 gene expression.

Ficolin-3 in chronic Chagas disease: Low serum levels associated with the risk of cardiac insufficiency.

AIMS: To investigate whether FCN3 polymorphisms and circulating ficolin-3 levels were associated with clinical forms of chronic Chagas disease (CD) and to assess their potential use as biomarkers for the disease or its severity. METHODS AND RESULTS: FCN3 polymorphisms (g.1637delC (rs532781899) in exon 5; g.3524_3532insTATTTGGCC (rs28362807) in intron 5 and g.4473C > A) (rs4494157) in intron 7) were determined in 178 chronic CD patients (65 asymptomatic, 68 cardiac, 21 digestive and 24 cardiodigestive), and 285 healthy controls by sequence-specific PCR. Ficolin-3 serum levels, measured by ELISA in 80 patients and 80 controls, did not differ between groups. On the other hand, ficolin-3 levels were positively correlated with left ventricular ejection fraction (P = .002; r = .5), with lower levels associated with increased risk of cardiac insufficiency (P = .033; OR 7.21, 95%IC 1.17-44.4). Ficolin-3 levels were positively correlated with ficolin-2 (P = .021; r = .63), and negatively with MBL (P = .002; r = -.36) and pentraxin-3 (P = .04; r = -.32) levels. No significant results were observed for the investigated FCN3 polymorphisms and CD. The g.1637del/1637C heterozygotes presented lower ficolin-3 levels than g.1637C/1637C homozygotes in the control group (P = .023). CONCLUSION: Low ficolin-3 levels may play a role in the pathophysiology of cardiac insufficiency associated with CD.

Effects of Euphorbia umbellata extracts on complement activation and chemotaxis of neutrophils.

ETHNOPHARMACOLOGICAL RELEVANCE: The species Euphorbia umbellata (leitosinha) has been traditionally used for the treatment of inflammatory diseases and cancer. AIM OF THE STUDY: Evaluation the effect of E. umbellata latex extracts obtained with hexane, chloroform, ethyl acetate and methanol on the activation of the complement pathways and neutrophil chemotaxis. MATERIALS AND METHODS: The latex was partitioned using Soxhlet apparatus and hexane, chloroform, ethyl acetate and methanol as solvents. The classical and alternative pathway activity were performed by hemolytic assays with sensitized sheep or rabbit erythrocytes, respectively; the lectin pathway activity was quantified by ELISA, through the measurement of C4 molecules and the chemotaxis of human neutrophils was performed using 1% casein as the chemotactic inducer and Boyden's chamber. GC-Q-ToF and NMR analyses were applied to evaluate the chemical composition of E. umbellata latex extracts. RESULTS: All E. umbellata latex extracts exhibited an inhibitory effect on the activation of the alternative pathway. Methanol and ethyl acetate extracts inhibited the classical pathway while chloroform extract activated this pathway. Ethyl acetate and hexane extracts inhibited lectin activation. All E. umbellata extracts inhibited casein-induced neutrophil chemotaxis. Terpenes and phenolic compounds have been suggested to be present in the E. umbellta latex extracts. CONCLUSION: The E. umbellata latex was able to modulate the functions of the immune system. Thus, it is possible to infer that the terpenes and phenolic compounds of the phytocomplex of E. umbellata latex can contribute for the activity on the complement pathways.

C3 Gene Functional Polymorphisms and C3 Serum Levels in Patients with Rheumatoid Arthritis.

The complement system is a key component of the innate immunity that plays a significant role in the development and clinical presentation of Rheumatoid arthritis (RA). Complement protein C3 is a central molecule in the activation of complement with a significant role in the inflammatory processes of RA. Nevertheless, the impact of C3 gene polymorphisms in the development of RA is still unknown. The current study aimed to investigate the possible influence of C3 gene polymorphisms in the susceptibility and clinical expression of RA. Three C3 polymorphisms (rs2250656:A > G, intron 2; rs2230199:C > G [p.Arg102Gly], exon 3 and rs1047286:C > T [p.Pro314Leu], exon 9) were assessed by sequence-specific PCR in a total of 156 RA patients and 270 healthy controls from Southern Brazil. In addition, C3 levels were measured in 60 patients and 60 controls by immunoturbidimetry and clinical features were collected from medical records. The frequency of rs2230199 G allele and GG genotype was significantly higher in RA patients than controls (padj = 0.012 OR = 1.57 [1.11-2.31]; padj = 0.008, OR = 1.60 [1.35-2.33]) as well as the rs1047286 T and TT (padj = 0.010, OR = 1.67 [1.12-2.40]; padj = 0.001, OR = 1.83 [1.27-2.65] and the C3 AGT haplotype (padj = 0.0007 OR = 1.92 [1.32-2.80]). Moreover, C3 serum levels were higher in patients than controls (median: 169 mg/dl vs.155 mg/dl; padj = 0.022), as well as in RF seronegative compared with seropositive patients (172 mg/dl vs. 165 mg/dl; padj = 0.007). Our results suggest that the rs2230199 G (p.102Gly) and rs1047286 T (p.314Leu) alleles play a role in the pathophysiology of RA, possibly impacting complement activation by the alternative pathway.