The polymorphisms of extracellular matrix-remodeling genes are associated with pelvic organ prolapse

Introduction and hypothesis Extracellular matrix (ECM) synthesis and metabolism abnormalities may influence the pelvic supporting system and lead to the occurrence and development of pelvic organ prolapse (POP). Genetic polymorphisms of such related genes have been increasingly studied. This study aims to explore the association between the single-nucleotide polymorphisms (SNPs) of genes encoding ECM processing enzymes (a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]), ECM degrading enzymes (matrix metalloproteinases [MMPs]) and their tissue inhibitors of metalloproteinase (TIMPs), and POP. Methods We conducted an association study including 48 women with POP at stages III and IV and 48 women without prolapse in Chinese groups. SNPs were identified using the target region sequencing technique. We performed Fisher’s exact tests to assess the association between SNPs and POP in the unadjusted model and logistic regression analysis in the adjusted model, adjusting for delivery and pregnancy. Results There was a significant association between TIMP2 SNP rs2277698 (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16–0.82; P = 0.015), ADAMTS13 SNP rs149586801 (OR, 0.18; 95% CI, 0.05–0.69; P = 0.012), and ADAMTS1 SNPs rs370850 and rs422803 (OR, 3.71; 95% CI, 1.35–10.15; P = 0.011 for both), rs402007, rs428785, rs434857, and rs445784 (OR, 2.18; 95% CI, 1.05–4.56; P = 0.038 for the four), and POP in the adjusted model. Conclusion TIMP2, ADAMTS13, and ADAMTS1 might be candidate genes for POP. Our results provide preliminarily new evidence for future investigation of these genes in the pathophysiology of POP.

Alteration of Extracellular Matrix Components in the Anterior Pituitary Gland of Neonatal Rats Induced by a Maternal Bisphenol A Diet during Pregnancy

The extracellular matrix (ECM) plays crucial roles in the anterior pituitary gland via the mechanism of cell–ECM interaction. Since bisphenol A (BPA), a well-known endocrine disruptor, can cross through the placenta from mother to fetus and bind with estrogen receptors, cell populations in the neonatal anterior pituitary gland could be the target cells affected by this chemical. The present study treated maternal rats with 5000 µg/kg body weight of BPA daily throughout the pregnancy period and then investigated the changes in ECM-producing cells, i.e., pericytes and folliculostellate (FS) cells, including their ECM production in the neonatal anterior pituitary at Day 1. We found that pericytes and their collagen synthesis reduced, consistent with the increase in the number of FS cells that expressed several ECM regulators—matrix metalloproteinase (MMP) 9 and the tissue inhibitors of metalloproteinase (TIMP) family. The relative MMP9/TIMP1 ratio was extremely high, indicating that the control of ECM homeostasis was unbalanced. Moreover, transmission electron microscopy showed the unorganized cell cluster in the BPA-treated group. This study revealed that although the mother received BPA at the “no observed adverse effect” level, alterations in ECM-producing cells as well as collagen and the related ECM balancing genes occurred in the neonatal anterior pituitary gland.

Comprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma

Background Tissue inhibitors of metalloproteinase (TIMP) family proteins are peptidases involved in extracellular matrix (ECM) degradation. Various diseases are related to TIMPs, and the primary reason is that TIMPs can indirectly regulate remodelling of the ECM and cell signalling by regulating matrix metalloproteinase (MMP) activity. However, the link between TIMPs and glioblastoma (GBM) is unclear. Objective This study aimed to explore the role of TIMP expression and immune infiltration in GBM. Methods Oncomine, GEPIA, OSgbm, LinkedOmics, STRING, GeneMANIA, Enrichr, and TIMER were used to conduct differential expression, prognosis, and immune infiltration analyses of TIMPs in GBM. Results All members of the TIMP family had significantly higher expression levels in GBM. High TIMP3 expression correlated with better overall survival (OS) and disease-specific survival (DSS) in GBM patients. TIMP4 was associated with a long OS in GBM patients. We found a positive relationship between TIMP3 and TIMP4, identifying gene sets with similar or opposite expression directions to those in GBM patients. TIMPs and associated genes are mainly associated with extracellular matrix organization and involve proteoglycan pathways in cancer. The expression levels of TIMPs in GBM correlate with the infiltration of various immune cells, including CD4+ T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. Conclusions Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.

POLYMORPHISM OF TISSUE INHIBITORS OF METALLOPROTEINASE-2 (G303 → A) GENE IN PATIENTS WITH INTESTINAL ANASTOMOTIC LEAK IN UKRAINIAN POPULATION

Purpose - to analyze the frequency of polymorphic variants of tissue inhibitors ofmetalloproteinase-2 (G303 → A) gene in patients with intestinal anastomotic leak.Material and methods. The object of the study comprises 61 patients with anastomotic leakand connective tissue pathology, who were treated in the department of thoracoabdominalsurgery of Shalimov National Institute of Surgery and Transplantology during 2017-2020. Laboratory, genetic, histological studies and statistical analysis were performed.Results. As a result of genetic and statistical analysis of the tissue inhibitors ofmetalloproteinase-2 (G303 → A) gene polymorphisms, genotype variants have beenidentified that are associated with the risk of anastomotic leak in the hollow digestiveorgans. Significant differences in the distribution of genotypes in the studied groupswere revealed. Analysis of the multiplicative model of inheritance of tissue inhibitors ofmetalloproteinase-2 (G303 → A) gene showed compliance of genotype distribution withHardy-Weinberg's law. All models of inheritance were analyzed and the best model withthe lowest Akaike Information Criterion, which turned out to be a recessive model, hasbeen determined.Conclusions. It is statistically significant that in the group of patients with intestinalanastomotic leak the GG variant of the TIMP-2 gene was detected in 1,6 times moreoften. Carriers of minor homozygotes of AA genotype in the group with suture failurewere not detected, while a similar genotype in the control group was found in 10%(p <0,05).

Change in Proteolytic Profile in Heifers After Oligofructose Overload

Laminitis in cattle is an important underlying cause of lameness, which leads to a significant reduction in economic and animal welfare. Nevertheless, the disordered pathological processes of laminitis remain unclear. Several proteinases are probably involved in the disorder of basement membrane (BM) metabolism in laminitis, for instance, matrix metalloproteinases (MMPs), neutrophil elastase (NE), and myeloperoxidase (MPO). This study aimed to investigate the change in proteolytic profile in circulating and lamellar tissues using an oligofructose (OF) overload-induced laminitis model in heifers. Twelve clinically healthy and nonlame Chinese Holstein heifers were recruited and randomly divided into two groups: OF-induced and control (CON). The OF-induced heifers group (n = 6) was administered 17 g/kg of body weight (BW) of OF dissolved in 2 L/100 kg of BW of tap water via the oral-rumen tube. The CON group (n = 6) was given an equal volume of tap water. The plasma samples were collected 0, 6, 12, 18, 24, 36, 48, 60, and 72 h after administration, and the lamellar samples were collected 72 h after euthanasia. The plasma samples were analyzed by zymography and reverse zymography. Histological examination, zymography, reverse zymography, and Western blot of lamellar samples were conducted. In the plasma of the OF-induced group, the pro-MMP9 activity increased from 36 h (P &lt; 0.001) to 60 h (P &lt; 0.05). Moreover, the plasma tissue inhibitors of metalloproteinase 1 (TIMP1) activity decreased after 18 h (P &lt; 0.05), while the ratio of pro-MMP9 to TIMP1 and TIMP2 increased after 18 h (P &lt; 0.001) and 48 h (P &lt; 0.05), respectively. The act-MMP2, pro-MMP9, and act-MMP9 activities increased in the lamellar tissue of the OF-induced group compared with the CON group (P &lt; 0.05). In addition, the expression of lamellar NE protein was higher in the OF-induced group (P &lt; 0.01), while no change was found in lamellar MPO protein compared with the CON group. In conclusion, increased pro-MMP9 combined with decreased TIMP1 activity in the circulation might have caused the activation of blood neutrophils, while the activation of proteolytic enzymes in lamellar tissue probably led to the dysfunction of BM in the OF-induced group.

Association between gene polymorphism of the tissue inhibitor matrix metalloproteinase-2 (G303→A) and enterocutaneous fistula

Objective – to analyze the frequency of polymorphic variants of tissue inhibitors of metalloproteinase-2 (G303→A) gene in patients with enterocutaneous fistula. Material and methods. The object of the study comprises 19 patients with enterocutaneous fistula who were treated in the Shalimov National Institute of Surgery and Transplantology during 2016-2019. Laboratory, genetic, histological studies and statistical analysis were performed.Results. As a result of genetic and statistical analysis of the tissue inhibitors of metalloproteinase-2 (G303→A) gene single nucleotide polymorphisms, genotype variants have been identified that are associated with the risk of enterocutaneous fistula development. All models of inheritance were analyzed and the best model with the lowest Akaike information criterion, which turned out to be a recessive model, has been determined.Conclusions. Enterocutaneous fistula is 1,58 times more common in carriers of homozygous GG genotype of the tissue inhibitors of metalloproteinase-2 (G303→A) gene and twice less common in heterozygotes GA (21,1% vs. 40%, p=0,057). Carriers of minor homozygotes of AA genotype in the group with enterocutaneous fistula were not detected, while a similar genotype in the control group was found in 10% of cases.

The MMP-2/TIMP-2 System in Alzheimer Disease

Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental, on AD, including: (1) MMP-2 directly degrades Aβ resulting in the clearance of Aβ deposits. Conversely, Aβ-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP- 2/TIMP-2 as therapeutic targets for AD.