First Trimester Placental Biomarkers for Pregnancy Outcomes.

The placenta plays a key role in several adverse obstetrical outcomes, such as preeclampsia, intrauterine growth restriction and gestational diabetes mellitus. The early identification of at-risk pregnancies could significantly improve the management, therapy and prognosis of these pregnancies, especially if these at-risk pregnancies are identified in the first trimester. The aim of this review was to summarize the possible biomarkers that can be used to diagnose early placental dysfunction and, consequently, at-risk pregnancies. We divided the biomarkers into proteins and non-proteins. Among the protein biomarkers, some are already used in clinical practice, such as the sFLT1/PLGF ratio or PAPP-A; others are not yet validated, such as HTRA1, Gal-3 and CD93. In the literature, many studies analyzed the role of several protein biomarkers, but their results are contrasting. On the other hand, some non-protein biomarkers, such as miR-125b, miR-518b and miR-628-3p, seem to be linked to an increased risk of complicated pregnancy. Thus, a first trimester heterogeneous biomarkers panel containing protein and non-protein biomarkers may be more appropriate to identify and discriminate several complications that can affect pregnancies.

The "Bad Father": Paternal Role in Biology of Pregnancy and in Birth Outcome.

Pregnancy is generally studied as a biological interaction between a mother and a fetus; however, the father, with his characteristics, lifestyle, genetics, and living environment, is by no means unrelated to the outcome of pregnancy. The half of the fetal genetic heritage of paternal derivation can be decisive in cases of inherited chromosomal disorders, and can be the result of de novo genetic alterations. In addition to the strictly pathological aspects, paternal genetics may transmit thrombophilic traits that affect the implantation and vascular construction of the feto-placental unit, lead to placenta-mediated diseases such as pre-eclampsia and fetal growth retardation, and contribute to the multifactorial genesis of preterm delivery. Biological aspects of immunological tolerance to paternal antigens also appear to be crucial for these pathologies. Finally, this review describes the biological findings by which the environment, exposure to pathogens, lifestyle, and nutritional style of the father affect fetal pathophysiological and epigenetic definition.

HELLP Syndrome and Differential Diagnosis with Other Thrombotic Microangiopathies in Pregnancy.

Thrombotic microangiopathies (TMAs) comprise a distinct group of diseases with different manifestations that can occur in both pediatric and adult patients. They can be hereditary or acquired, with subtle onset or a rapidly progressive course, and they are particularly known for their morbidity and mortality. Pregnancy is a high-risk time for the development of several types of thrombotic microangiopathies. The three major syndromes are hemolysis, elevated liver function tests, and low platelets (HELLP); hemolytic uremic syndrome (HUS); and thrombotic thrombocytopenic purpura (TTP). Because of their rarity, clinical information and therapeutic results related to these conditions are often obtained from case reports, small series, registries, and reviews. The collection of individual observations, the evolution of diagnostic laboratories that have identified autoimmune and/or genetic abnormalities using von Willebrand factor post-secretion processing or genetic-functional alterations in the regulation of alternative complement pathways in some of these TMAs, and, most importantly, the introduction of advanced treatments, have enabled the preservation of affected organs and improved survival rates. Although TMAs may show different etiopathogenesis routes, they all show the presence of pathological lesions, which are characterized by endothelial damage and the formation of thrombi rich in platelets at the microvascular level, as a common denominator, and thrombotic damage to microcirculation pathways induces "mechanical" (microangiopathic) hemolytic anemia, the consumption of platelets, and ischemic organ damage. In this review, we highlight the current knowledge about the diagnosis and management of these complications during pregnancy.

Mechanisms of action of mineral fibres in a placental syncytiotrophoblast model: An in vitro toxicology study.

Asbestos has been widely used due to its unique characteristics. It is known that exposure to asbestos causes serious damage to health but one species, chrysolite, is still used because it is considered less toxic and not biopersistent in some countries. The aim of our study was to investigate if cellular process underlying the proliferation, differentiation and cell death of placental tissues could be modify in presence of asbestos fibres (50 µg/ml final concentration), long chrysolite fibres (CHR-L) and short chrysolite fibres (CHR-S), using BeWo cell line, an in vitro model that mimics the syncytiotrophoblast (STB), the outer layer of placental villi. Our data demonstrated that none of the fibres analysed alter syncytiotrophoblast formation but all of them induce ROS formation and reduced cell proliferation. Moreover, we showed that only CHR-L fibre induced was able to induce irreversible DNA alterations that carried cells to apoptosis. In fact, BeWo cells exposed to CHR-L fibre showed a significant increase in cleaved CASP3 protein, a marker of apoptosis. These data suggest that CHR-L may induce death of the placental villi leading to impaired placental development. The impairment of placental development is the basis of many gestational pathologies such as preeclampsia and intrauterine growth retardation. Since these pathologies are very dangerous for foetal and maternal life, we suggest to the gynaecologists to carefully evaluate the area of maternal residence, the working environment, the food used, and the materials used daily to avoid contact with these fibres as much as possible.

Circulating miRNAs and Preeclampsia: From Implantation to Epigenetics.

In this review, we comprehensively present the literature on circulating microRNAs (miRNAs) associated with preeclampsia, a pregnancy-specific disease considered the primary reason for maternal and fetal mortality and morbidity. miRNAs are single-stranded non-coding RNAs, 20-24 nt long, which control mRNA expression. Changes in miRNA expression can induce a variation in the relative mRNA level and influence cellular homeostasis, and the strong presence of miRNAs in all body fluids has made them useful biomarkers of several diseases. Preeclampsia is a multifactorial disease, but the etiopathogenesis remains unclear. The functions of trophoblasts, including differentiation, proliferation, migration, invasion and apoptosis, are essential for a successful pregnancy. During the early stages of placental development, trophoblasts are strictly regulated by several molecular pathways; however, an imbalance in these molecular pathways can lead to severe placental lesions and pregnancy complications. We then discuss the role of miRNAs in trophoblast invasion and in the pathogenesis, diagnosis and prediction of preeclampsia. We also discuss the potential role of miRNAs from an epigenetic perspective with possible future therapeutic implications.

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 Xc- 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.

First Trimester CD93 as a Novel Marker of Preeclampsia and Its Complications: A Pilot Study.

INTRODUCTION: CD93 plays a crucial role in endothelial homeostasis and angiogenesis. Recently its role in hypertension has been investigated, holding promise for novel targeted diagnostic and therapeutic strategies. AIM: We assessed for the first time differences in first trimester serum CD93 levels in women who lately developed preeclampsia (PE) vs. normotensive pregnancy (NP). METHODS: First trimester serum CD93 concentrations were assessed in a multicenter cohort of 83 women (34 PE and 49 NP) by ELISA Immunoassay. RESULTS: Serum CD93 was lower in women who developed PE vs. NP (111.8 ± 24.4 vs. 137.5 ± 22.3 ng/ml; p < 0.001). Serum CD93 was associated with a decreased risk of developing PE (OR 0.950, 95% CI 0.922-0.978) and composite neonatal outcome (OR 0.952, CI 0.923-0.982), after adjustment for confounders. CONCLUSIONS: PE is accompanied by decreased serum CD93 levels. CD93 might play a role during placentation leading to defective angiogenesis, vascular dysfunction, and PE development.

Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells.

Role of CD93 in Health and Disease.

CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.

Melanoma and subcutaneous adipose tissue: Role of peritumoral adipokines in disease characterization and prognosis.

In the last decades, the concept of adipose organ has emerged, giving adipose tissue an active endocrine and immunologic function through the secretion of multiple cytokines and chemokines that seem to be implicated in the development and progression of several cancer, including cutaneous melanoma. In this pilot experimental study, we analyzed the expression in the peritumor subcutaneous adipose tissue of the most significant adipokines involved in the processes of carcinogenesis and metastasis in a population of melanoma patients and in two control groups composed of melanocytic nevi and epidermoid cysts, respectively. We correlated the results obtained with the main disease prognostic factors observing a statistically significant increase in the expression of PAI1, LEP, CXCL1, NAMPT, and TNF-α at the level of the peritumor tissue of the melanoma samples compared to the control groups and a correlation of the same with the histopathological prognostic factor of melanoma. Our preliminary study shows that the overexpression of PAI1, LEP, CXCL1, NAMPT, and TNF-α may contribute to the growth and to the local aggressiveness of cutaneous melanoma. It opens the hypothesis of a direct oncogenic role of subcutaneous adipose tissue and adipokines in the tumorigenesis of melanoma.

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.

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.

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.

HTRA1 in Placental Cell Models: A Possible Role in Preeclampsia.

The HtrA serine peptidase 1 (HTRA1) is a multidomain secretory protein with serine-protease activity involved in the regulation of many cellular processes in both physiological and pathological conditions. HTRA1 is normally expressed in the human placenta, and its expression is higher in the first trimester compared to the third trimester, suggesting an important role of this serine protease in the early phases of human placenta development. The aim of this study was to evaluate the functional role of HTRA1 in in vitro models of human placenta in order to define the role of this serine protease in preeclampsia (PE). BeWo and HTR8/SVneo cells expressing HTRA1 were used as syncytiotrophoblast and cytotrophoblast models, respectively. Oxidative stress was induced by treating BeWo and HTR8/SVneo cells with H2O2 to mimic PE conditions in order to evaluate its effect on HTRA1 expression. In addition, HTRA1 overexpression and silencing experiments were performed to evaluate the effects on syncytialization, cell mobility, and invasion processes. Our main data showed that oxidative stress significantly increased HTRA1 expression in both BeWo and HTR8/SVneo cells. In addition, we demonstrated that HTRA1 has a pivotal role in cell motility and invasion processes. In particular, HTRA1 overexpression increased while HTRA1 silencing decreased cell motility and invasion in HTR8/SVneo cell model. In conclusion, our results suggest an important role of HTRA1 in regulating extravillous cytotrophoblast invasion and motility during the early stage of placentation in the first trimester of gestation, suggesting a key role of this serine protease in PE onset.

The Role of NQO1 in Ovarian Cancer.

Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance onset. Several researchers reported that oxidative stress plays a key role in ovarian cancer occurrence, growth and development. The NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that, using NADH or NADPH as substrates to reduce quinones to hydroquinones, avoids the formation of the highly reactive semiquinones, then protecting cells against oxidative stress. In this review, we report evidence from the literature describing the effect of NQO1 on ovarian cancer onset and progression.

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.

Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers.

Cervical and endometrial cancers are among the most dangerous gynaecological malignancies, with high fatality and recurrence rates due to frequent diagnosis at an advanced stage and chemoresistance onset. The NRF2/KEAP1 signalling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. NRF2, activated by ROS, induces the expression of antioxidant enzymes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase which neutralize ROS, protecting cells against oxidative stress damage. However, activation of NRF2/KEAP1 signalling in cancer cells results in chemoresistance, inactivating drug-mediated oxidative stress and protecting cancer cells from drug-induced cell death. We review the literature on the role of the NRF2/KEAP1 pathway in cervical and endometrial cancers, with a focus on the expression of its components and downstream genes. We also examine the role of the NRF2/KEAP1 pathway in chemotherapy resistance and how this pathway can be modulated by natural and synthetic modulators.

ZO-1 expression in normal human macula densa: Immunohistochemical and immunofluorescence investigations.

The macula densa (MD) is an anatomical structure having a plaque shape, placed in the distal end of thick ascending limb of each nephron and belonging to juxtaglomerular apparatus (JGA). The aim of the present investigation is to investigate the presence of ZO-1, a specific marker of tight juncions (TJs), in MD cells. Six samples of normal human renal tissue were embedded in paraffin for ZO-1 expression analysis by immunohistochemical and immunofluorescence techniques. We detected ZO-1 expression in the apical part of cell membrane in MD cells by immunohistochemistry. In addition, ZO-1 and nNOS expressions (a specific marker of MD) were colocalized in MD cells providing clear evidence of TJs presence in normal human MD. Since ZO-1 is responsible for diffusion barrier formation, its presence in the MD supports the existence of a tubulomesangial barrier that ensures a regulated exchange between MD and JGA effectors in renal and glomerular haemodynamic homeostasis.

NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis. METHODS AND RESULTS: We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention. CONCLUSION: We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis.