Diagnostic and Prognostic Role of CD93 in Cardiovascular Disease: A Systematic Review

Introduction. Cluster of Differentiation (CD) 93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp) is a transmembrane glycoprotein that can also be present in a soluble (sCD93) form. Recent studies have investigated the role of this protein in cardiovascular disease (CVD). The present systematic review aims to assess the associations between CD93 and cardiovascular (CV) risk factors and disease at both the proteomic and genomic levels. Methods. We conducted systematic searches in the PubMed, EMBASE, and Web of Science databases to identify all human studies since inception to February 2023 that investigated the role of CD93 in CV risk factors, CVD, and CV-associated outcomes. The data collection and analysis have been independently conducted by two reviewers. The search terms included: cardiovascular, heart failure, acute stroke, myocardial infarction, stroke, peripheral artery disease, cardiovascular death, MACE, hypertension, metabolic syndrome, hyperuricemia, diabetes, cd93, c1qr, C1qR1, complement protein 1 q subcomponent receptor. Results. A total of 182 references were identified, and 15 studies investigating the associations between CD93 protein levels or CD93 genetic polymorphisms and the development or prevalence of CV risk factors (i.e., hypertension, dyslipidemia, and obesity) and CVD (i.e., heart failure, coronary artery disease, and ischemic stroke) were included. Although promising, the quality and dimension of the analyzed studies do not allow for a definitive answer to the question of whether CD93 may hold diagnostic and prognostic value in CVD

Modulation of NRF2/KEAP1 Signaling in Preeclampsia

Placentation is a key and tightly regulated process that ensures the normal development of the placenta and fetal growth. Preeclampsia (PE) is a hypertensive pregnancy-related disorder involving about 5–8% of all pregnancies and clinically characterized by de novo maternal hypertension and proteinuria. In addition, PE pregnancies are also characterized by increased oxidative stress and inflammation. The NRF2/KEAP1 signaling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. ROS activate NRF2, allowing its binding to the antioxidant response element (ARE) region present in the promoter of several antioxidant genes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase that neutralize ROS, protecting cells against oxidative stress damages. In this review, we analyze the current literature regarding the role of the NRF2/KEAP1 pathway in preeclamptic pregnancies, discussing the main cellular modulators of this pathway. Moreover, we also discuss the main natural and synthetic compounds that can regulate this pathway in in vivo and in vitro models

CD93 A POTENTIAL PLAYER IN CYTOTROPHOBLAST AND ENDOTHELIAL CELL MIGRATION

CD93, also known as complement component C1q receptor, is expressed on the surface of diferent cellular types such as monocytes, neutrophils, platelets, microglia, and endothelial cells, and it plays a pivotal role in cell proliferation, cell migration, and formation of capillary-like structures. These processes are strictly regulated, and many fetal and maternal players are involved during placental development. At present, there are no studies in literature regarding CD93 in placental development, so we investigated CD93 expression in frst and third trimester and PE placentas by immunohistochemistry and western blotting analysis. In addition, we performed in vitro experiments under oxidative stress conditions to demonstrate how oxidative stress acts on CD93 protein expression. Our data showed that CD93 was expressed in villous cytotrophoblast cells, in some fetal vessels of frst and third trimester and PE placentas and in the extravillous cytotrophoblast of cell columns in the frst trimester placentas. Moreover, we detected a signifcant decrease of CD93 expression in third trimester and PE placentas compared to frst trimester placentas, while no diferences were detected between third and PE placentas. No diferences of CD93 expression were detected in oxidative stress conditions. We suggest that CD93 can guide extravillous cytotrophoblast migration through β1-integrin in uterine spiral arteries during placentation in the frst trimester of pregnancy and that the decrease of CD93 expression in third trimester and PE placentas could be linked to the poor extravillous cytotrophoblast cells migration. So, it might be interesting to understand the role of CD93 in the frst phases of PE onset

HTRA family proteins in pregnancy outcome

HTRA (High temperature requirement protease A) family proteins includes HTRA1 (L56 or PRSS11), HTRA2/Omi, HTRA3 (PRSP) and HTRA4. These are oligomeric serine proteases highly conserved from bacteria to humans and are involved in a variety of biological functions including the maintenance of normal cell physiology and pathogenicity such as cell growth, apoptosis, neurodegenerative disorders, inflammation diseases and cancer. These proteins are normally expressed in placental villi during all pregnancy but their expression is found to be altered in pathological pregnancies suggesting a possible role of those proteins in the development of human placenta. Moreover, some HTRA family proteins have also been found in maternal blood and were impaired in pathological pregnancy suggesting a possible role of some of these proteins as early markers of pregnancy outcome. The aim of this review is to summarize the data currently available on the role of HTRA family proteins in pregnancy focalizing their role in pregnancy complications such as Preeclampsia (PE), IntraUterine Growth Restriction (IUGR) and Spontaneus PreTerm Birth (SPTB)

Role of SLC7A11/xCT in Ovarian Cancer

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the (Formula presented.) system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target

Serum uric acid to creatinine ratio and risk of preeclampsia and adverse pregnancy outcomes

Objective: Preeclampsia is one of the most severe diseases among the hypertensive disorders of pregnancy (HDP) and the leading cause of maternal and fetal morbidity and mortality. It is of crucial importance to early identify women at a high risk for preeclampsia to implement appropriate preventive strategies. In our study, we aimed to test the hypothesis that serum uric acid to creatinine ratio (SUA/sCr) is related to the development of preeclampsia and maternal and neonatal complications. Methods: We searched for uric acid and creatine values in the medical records of 269 women who consecutively attended our HDP Clinic from December 2018 to December 2022. We compared the baseline characteristics of participants with normotensive pregnancy ( n  = 57), to those with HDP without preeclampsia (HDP-non-PE) ( n  = 100) and those with preeclampsia ( n  = 112), and we performed adjusted logistic regression analysis to test the associations between SUA/sCr and the development of preeclampsia and maternal and neonatal complications. Results: SUA/sCr was consistently higher in women with preeclampsia in all trimesters of pregnancy. Higher SUA/sCr at the third trimester was associated with an increased odd of developing preeclampsia [odds ratio (OR) 1.29, confidence interval (CI) 1.15-1.50, P  = 0.001], preterm birth (OR 1.23, CI 1.05-1.45, P  = 0.011), and composite neonatal outcome (OR 1.33, CI 1.12-1.59, P  = 0.001), after adjustment for age, BMI before pregnancy, nulliparity, antihypertensive therapy, and acetylsalicylic acid therapy during pregnancy. Conclusions: Having higher SUA/sCr during pregnancy is associated with the development of PE and adverse pregnancy outcomes. Controlled prospective studies are warranted to clarify the predictive power of this novel marker during pregnancy

Possible involvement of HtrA1 serine protease in the onset of osteoporotic bone extracellular matrix changes

High-temperature requirement A1 (HtrA1), a multidomain serine protease acting on Extracellular matrix (ECM) rearrangement, is also secreted by osteoblasts and osteoclasts. Recent and conflicting literature highlights HtrA1's role as a controller of bone remodeling, proposing it as a possible target for pathologies with unbalanced bone resorption, like Osteoporosis (OP). To add knowledge on this molecule function in bone physiopathology, here we compared HtrA1 distribution in the ECM of healthy (H) and OP bone tissue, also examining its localization in the sites of new bone formation. HtrA1 was homogeneously expressed in the mature bone ECM of H tissue showing a 55.6 ± 16.4% of the stained area, with a significant (p=0.0001) decrease in OP percentage stained area (21.1 ± 13.1). Moreover, HtrA1 was present in the endosteum and cells involved in osteogenesis, mainly in those "entrapped" in woven bone, whereas osteocytes in mature lamellar bone were negative. Based on our previous observation in OP tissue of a significantly increased expression of Decorin and Osteocalcin, both involved in bone mineralization and remodeling and equally substrates for HtrA1, we speculate that HtrA1 by controlling the proper amount of Decorin and Osteocalcin favors normal bone maturation and mineralization. Besides, we suggest that late-osteoblasts and pre-osteocytes secrete HtrA1 in the adjacent matrix whilst proceeding with their maturation and that HtrA1 expression is further modified during the remodeling from woven to the lamellar bone. Overall, our data suggest HtrA1 as a positive regulator of bone matrix formation and maturation: its reduced expression in mature OP bone, affecting protein content and distribution, could hamper correct bone remodeling and mineralization

High temperature requirement A1 and fibronectin: two possible players in placental tissue remodelling

<p>High temperature requirement A1 (HtrA1) is a secreted protease involved in placental development. Fibronectin (FN) is involved in important process such as wound healing, cell adhesion and spreading, growth, migration, and differentiation. The purpose of this study was to analyse the expression patterns of HtrA1 in relationship to FN and to the key growth zones of placenta such as mesenchymal villi as well as cell islands and cell columns. We demonstrated that FN and HtrA1 are localized in the placental key growth zones suggesting a pivotal role in maintaining the balance among the molecules involved in the placental development and differentiation.</p

Identification of multinucleated cells in human kidney cortex: A way for tissue repairing?

The presence of multinucleated cells has never been demonstrated in renal tissue, although, polyploid cells were recently observed in the tubules of normal and pathological human kidney. Therefore, the aim of the present study is to identify and quantify, by electron microscopy, multinucleated cells in the cortical tissue of normal human kidney i.e., in the three compartments of renal tubule: the proximal tubule (PT), the distal tubule (DT), and the collecting duct (CD), as well as, in the glomerulus (podocytes). The percentage of the multinucleated cells observed was 5% (95%CI: 3.6%–6.7%) in renal cortical tubules with distribution in each tubular compartment of 6% in PT, 4% in DT and 3% in CD with no statistically significant difference in the distribution of multinucleated cells according to tubular compartments. Four percent of analysed podocytes (in total 149 podocytes) were multinucleated (95%CI: 1.5%−8.6%). In conclusion, multinucleated cells were identified and quantified in functionally normal kidneys, as previously demonstrated in other organs such as the liver

Downregulation of argininosuccinate synthase 1 (ASS1) is associated with hypoxia in placental development

Argininosuccinate synthase (ASS1) is involved in nitric oxide production, which has a key role in placental development improving pregnancy outcomes. Syncytiotrophoblast and extravillous trophoblast differentiations are milestones of placental development and their impairment can cause pathologies, such as preeclampsia (PE) and fetal growth restriction (FGR). Immunohistochemistry and Western blotting were used to localize and quantify ASS1 in first trimester (8.2 +/- 1.8 weeks), third trimester (38.6 +/- 1.1 weeks), and PE (36.3 +/- 1.5 weeks) placentas. In addition, cell cultures were used to evaluate ASS1 expression under hypoxic conditions and the syncytialization process. Our data showed that ASS1 is localized in the villous cytotrophoblast of first trimester, third trimester, and PE placentas, while the villous cytotrophoblast adjacent to the extravillous trophoblast of cell columns as well as the extravillous trophoblast were negative for ASS1 in first trimester placentas. In addition, ASS1 was decreased in third trimester compared to the first trimester placentas (p = 0.003) and no differences were detected between third trimester and PE placentas. Moreover, ASS1 expression was decreased in hypoxic conditions and syncytialized cells compared to those not syncytialized. In conclusion, we suggest that the expression of ASS1 in villous cytotrophoblast is related to maintaining proliferative phenotype, while ASS1 absence may be involved in promoting the differentiation of villous cytotrophoblast in extravillous cytotrophoblast of cell columns in first trimester placentas