Influence of Matrix Metalloproteinases MMP-2, -3 and on Age- Related Macular Degeneration Development

Age-related macular degeneration (AMD) is the leading cause of significant and irreversible central visual loss as it affects a small area of the retina, called the macula. However, the pathogenesis of still fairly understood. AMD has a multifactorial etiology, and its development might be influenced by body peculiarities, environmental and genetic factors. Risk factors such as age, gender, cigarette smoking, color of iris, nutrition, body mass index, oxidative stress, and genetic factors (complement factor H gene, Apo E gene, matrix metalloproteinases (MMPs) genes and others) increase probability to develop AMD. Here, we discuss about choroidal neovascularization process, where hypoxia, inflammatory process, and proteolytic enzymes play a main role, but mainly we focus on the family of matrix metalloproteinases (MMPs), especially on MMP -2, -3 and -9, and their impact on AMD development. MMPs belong to a family of proteolytic zinc-containing enzymes, and their mechanism under normal physiological conditions is precisely regulated, but when is dysregulated, MMPs become a cause of various diseases, including and AMD. MMPs are capable of degrading most of the extracellular matrix components, which are important in the remodeling during angiogenesis. Angiogenesis is the main pathological process associated with age-related macular degeneration development. Activated endothelial cells release MMPs which by degrading the basilar membrane allows capillaries to grow beneath the retina and retinal layers. Such capillaries often bleed, more liquids are filtered through the walls, and fibrous tissue grows within. Furthermore, swelling of the retina and impaired vision occur. In this book chapter, we focus on AMD prevalence, risk factors, clinics, diagnostics and influence of MMP-2, -3 and -9 on AMD development

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients’ plasma

Funding Information: The financial support given by NSFC with Grant No. 11874034, Taishan Scholar Program of Shandong No. ts201712054, and Shandong Science and Technology Enterprise Innovation Capacity Enhancement Project (2021TSGC1036) are highly appreciated for this research. Publisher Copyright: Copyright © 2022 Niedra, Peculis, Litvina, Megnis, Madrika, Balcere, Romanovs, Steina, Stukens, Breiksa, Nazarovs, Sokolovska, Liutkeviciene, Vilkevicute, Konrade and Rovite.Background: Circulating plasma miRNAs have been increasingly studied in the field of pituitary neuroendocrine tumor (PitNET) research. Our aim was to discover circulating plasma miRNAs species associated with growth hormone (GH) secreting PitNETs versus assess how the plasma levels of discovered miRNA candidates are impacted by SSA therapy and whether there is a difference in their levels between GH secreting PitNETs versus other PitNET types and healthy individuals. Design: We compared plasma miRNA content and levels before and after surgery focusing on GH secreting PitNET patients. Selected miRNA candidates from our data and literature were then tested in a longitudinal manner in somatostatin analogues (SSA) treatment group. Additionally, we validated selected targets in an independent GH secreting PitNET group. Methods: miRNA candidates were discovered using the whole miRNA sequencing approach and differential expression analysis. Selected miRNAs were then analyzed using real-time polymerase chain reaction (qPCR). Results: Whole miRNA sequencing discovered a total of 16 differentially expressed miRNAs (DEMs) in GH secreting PitNET patients’ plasma 24 hours after surgery and 19 DEMs between GH secreting PitNET patients’ plasma and non-functioning (NF) PitNET patients’ plasma. Seven miRNAs were selected for further testing of which miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p showed a significant downregulation in plasma after 1 month of SSA treatment. mir-625-5p was found to be significantly downregulated in plasma of GH secreting PitNET patients vs. NF PitNET patients. miR-625-5p alongside miR-130b-3p were also found to be downregulated in GH PitNETs compared to healthy individuals. Conclusions: Our study suggests that expression of plasma miRNAs miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p in GH secreting PitNETs is affected by SSA treatment. Additionally, miR-625-5p can distinguish GH secreting PitNETs from other PitNET types and healthy controls warranting further research on these miRNAs for treatment efficacy.publishersversionPeer reviewe

<i>VEGFA</i> Haplotype and VEGF-A and VEGF-R2 Protein Associations with Exudative Age-Related Macular Degeneration

Our study aimed to reveal the associations between VEGFA SNPs (rs1570360, rs699947, rs3025033, and rs2146323), their haplotypes, VEGF-A and VEGF-R2 serum concentrations, and early and exudative AMD. A total of 339 subjects with early AMD and 419 with exudative AMD groups, and 374 healthy subjects, were genotyped for four VEGFA SNPs (rs1570360, rs699947, rs3025033, and rs2146323). VEGF-A and VEGFR-2 serum concentrations were measured in exudative AMD and controls. The results revealed that rs3025033 G allele was significantly associated with lower odds of exudative AMD under the dominant model (OR = 0.67; 95% CI: 0.49–0.80; p = 0.0088) and additive (OR = 0.7; 95% CI: 0.54–0.90; p = 0.0058) models after Bonferroni correction. In the female group, rs3025033 AG genotype was associated with exudative AMD under the codominant model (OR = 0.57; 95% CI: 0.37–0.87; p = 0.009) and G allele under the dominant (OR = 0.55; 95% CI: 0.37–0.82; p = 0.0032) and additive models (OR = 0.60; 95% CI: 0.42–0.84; p = 0.0028). Haplotype analysis revealed that individuals carrying rs1570360, rs699947, rs3025033, and rs2146323 haplotype A-A-G-A had decreased risk of exudative AMD (OR = 0.46, 95% CI: 0.23–0.90; p = 0.023). The VEGF-A and VEGF-R2 serum concentrations did not differ between study groups; we found that patients with exudative AMD carrying at least one C allele at rs699947 have statistically significantly higher VEGF-A serum concentrations compared to AA genotype carriers (485.95 (945.93) vs. 194.97 (-), respectively, p = 0.046). In conclusion, we found that VEGFA rs3025033 and haplotype rs1570360A-rs699947A-rs3025033G- rs2146323A play a protective role for exudative AMD in the Caucasian population. Furthermore, rs699947 is associated with elevated VEGF-A serum concentrations in exudative AMD

Association of exudative age-related macular degeneration with matrix metalloproteinases-2 (-1306 C/T) rs243865 gene polymorphism

Purpose: Age-related macular degeneration (AMD) is a disease of the macula that significantly affects eyesight and leads to irreversible central vision loss. Recent studies have demonstrated that angiogenesis is the most important mechanism of AMD development. It is associated with extracellular remodeling involving different proteolytic systems, among them matrix metalloproteinases (MMPs), which play an essential role in the etiopathogenesis of AMD. The main objective of the present study was to determine the relationship between exudative AMD and MMP-2 (-1306 C/T) rs243865 polymorphism. Methods: The study enrolled 267 patients with exudative AMD and 318 controls. DNA was extracted from peripheral venous blood leukocytes by commercial kits. Genotyping of MMP-2 (-1306 C/T) rs243865 was carried out using real-time polymerase chain reaction method. Results: The analysis of MMP-2 (-1306 C/T) polymorphism did not reveal any differences in the distribution of CC, CT, and TT genotypes between the exudative AMD and control groups: 58.8%, 31.5% and 9.7% vs. 59.75%, 33.96% and 6.29%, respectively, P = 0.287). When the study population was subdivided into age groups, MMP-2 (-1306 C/T) rs243865 CT genotype showed 5.7-fold increased the risk of exudative AMD development compared to CC and TT genotypes together in younger (<65 years) males group (P = 0.05). Conclusion: MMP-2 (-1306 C/T) polymorphism is associated with exudative AMD development in younger males

IL-9 and IL-10 Single-Nucleotide Variants and Serum Levels in Age-Related Macular Degeneration in the Caucasian Population

Considering the immunological impairment in age-related macular degeneration (AMD), we aimed to determine the associations of IL-9 rs1859430, rs2069870, rs11741137, rs2069885, and rs2069884 and IL-10 rs1800871, rs1800872, and rs1800896 polymorphisms and their haplotypes, as well as the serum levels of IL-9 and IL-10 with AMD. 1209 participants were enrolled in our study. SNPs were genotyped using TaqMan SNP genotyping assays by real-time PCR method. IL-9 and IL-10 serum levels were evaluated using ELISA kits. Our study results have shown that haplotypes A-G-C-G-G and G-A-T-A-T of IL-9 SNPs are associated with the decreased odds of early AMD occurrence (p=0.035 and p=0.015, respectively). A set of rare haplotypes was associated with the decreased odds of exudative AMD occurrence (p=0.033). Also, IL-10 serum levels were lower in exudative AMD than in controls (p=0.049), patients with early AMD (p=0.017), and atrophic AMD (p=0.008). Furthermore, exudative AMD patients with IL-10 rs1800896 CT and TT genotypes had lower IL-10 serum concentrations than those with wild-type (CC) genotype (p=0.048). In conclusion, our study suggests that IL-10 serum levels can be associated with a minor allele at IL-10 rs1800896 and exudative AMD. The haplotypes of IL-9 SNPs were also associated with the decreased odds of early and exudative AMD