Miguel Angel Saez

Background: Late-onset preeclampsia (LO-PE) is the most prevalent clinical phenotype of preeclampsia and, although traditionally considered less strongly associated with placental dysfunction than early-onset disease, increasing evidence supports the presence of relevant placental alterations. The extracellular matrix (ECM) is a key regulator of villous architecture, tissue mechanics, trophoblast behavior, vascular remodeling, and angiogenesis. This study aimed to characterize ECM remodeling in placentas from women with LO-PE. Patients and Methods: A prospective observational study was conducted in 111 pregnant women, including 68 with LO-PE and 43 healthy controls. Placental samples were collected immediately after delivery. Gene expression of elastogenesis-related markers, cross-linking enzymes, fibrillar collagens, matrix-remodeling regulators, and endothelial–matrix signaling molecules was assessed by RT-qPCR. Protein expression was evaluated by immunohistochemistry. Differences between groups were analyzed using non-parametric tests with Benjamini–Hochberg correction, and correlations among ECM markers were explored using Spearman analysis. Results: LO-PE placentas showed significantly increased expression of tropoelastin (TE), fibulin-4 (FBLN-4), fibulin-5 (FBLN-5), fibrillin-1 (FBN-1), lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL-1), collagen type I (COL-I), collagen type III (COL-III), and matrix metalloproteinase-2 (MMP-2) at both gene and protein levels. Conversely, gene and protein expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) and epidermal growth factor-like domain 7 (EGFL7) showed a marked decrease in the placentas of pregnant women with LO-PE. These findings indicate enhanced elastogenesis, increased matrix cross-linking, greater fibrillar collagen deposition, and an imbalance in matrix turnover. Correlation analysis further suggested that, although the FBLN-4/FBLN-5 axis remained preserved, LO-PE placentas displayed partial disruption of the broader ECM transcriptional network. Conclusions: LO-PE placentas exhibit a coordinated but dysregulated ECM remodeling phenotype involving elastic, collagenous, proteolytic, and endothelial–matrix regulatory pathways. These alterations support ECM remodeling as a relevant biological feature of LO-PE placental pathophysiology.

Maternal psychoactive substance use during pregnancy represents a major threat to placental integrity and fetal development. As the central interface for maternal–fetal exchange, the placenta is highly susceptible to psychoactive substances, including alcohol, tobacco, cannabis, cocaine, opioids, and synthetic drugs, which can cross the placental barrier and induce structural and functional alterations. This review synthesizes current evidence on the biological mechanisms, diagnostic approaches, and forensic relevance of psychoactive substances-induced placental pathology. We summarize how different substances disrupt placental vascularization, oxidative balance, epigenetic regulation, and cellular viability, leading to impaired nutrient and oxygen transfer and increasing the risk of adverse outcomes such as intrauterine growth restriction, preterm birth, congenital anomalies, and long-term neurodevelopmental impairment. We further discuss the role of placental tissue in identifying prenatal drug exposure and reconstructing exposure timelines. Beyond its clinical relevance, placental examination provides objective evidence with potential forensic value in cases of suspected maternal substance use, while also informing non-punitive, evidence-based interventions. Overall, integrating placental pathology into reproductive health research and prenatal care offers a multidisciplinary framework to improve maternal–fetal outcomes and guide public health strategies addressing substance use during pregnancy.

Background: Chronic venous disease (CVD) is a vascular disorder common among pregnant women, due to the impairment in the venous function associated with the mechanical, hemodynamical, and hormonal changes that occur during pregnancy. CVD is linked to venous hypertension, inflammation, oxidative stress, and hypoxia, which alter placental structure and function, as demonstrated in previous works. The placenta fulfills several roles in fetal development and maternal well-being by mediating nutrient exchange; acting as a mechanical, chemical, and immunological shield; and producing essential hormones, making it crucial to investigate the effects of CVD in this organ. Patients and methods: This work specifically analyzes the gene expression of circadian markers (CLOCK, BMAL1, PER1, and PER2), epigenetic regulators (HAT1 and associated molecules like histones H3, H4, RBBP7, and ASF1), and the anti-aging protein KLOTHO in placental tissue of pregnant women with CVD (CVD-PW, N = 98) compared to healthy pregnant controls (HC-PW, N = 82), using RT-qPCR and immunohistochemistry (IHC) to determine protein expression. Results: Our study demonstrates that the placentas of CVD-PW exhibit the reduced gene and protein levels of circadian regulators (clock, bmal1, per1, and per2), increased expression of hat1 and related proteins (h3, h4, rbbp7, and asf1), and decreased klotho expression, indicative of accelerated aging. Conclusions: These findings highlight profound molecular disturbances in the placentas of women with CVD, offering insights into the disease’s pathophysiology and potential implications for maternofetal well-being. While this study deepens our understanding of the relationship between CVD and placental dysfunction, further research is required to fully elucidate these mechanisms and their long-term effects.

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho’s role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho’s multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses.

Background: Chronic venous disease (CVD) comprises a set of vascular disorders that affect the venous system with important local and systemic repercussions. A growing body of evidence displays the relationship between suffering from CVD and a marked deregulation of the immune inflammatory system. In this sense, the previous literature has reported some significant changes in the level of various circulating inflammatory parameters in these patients. However, more research is required to detail and deepen this complex relationship. Methods: In this work, we studied, using a multiplex technique, the levels of circulating cytokines and chemokines detectable in the serum of 40 patients with CVD and compared it with 38 healthy controls (HCs). In parallel, we performed Spearman’s correlation analysis to explore potential inflammatory networks in CVD. Results: In this study, we measured circulating cytokines and chemokines in CVD patients using a multiplex assay. Results showed increased levels of several pro-inflammatory mediators (IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, IL-17A, IL-23, TNF-α, IFN-γ, fractalkine, ITAC, and GM-CSF) and a decrease in IL-13, with no significant changes in IL-4, IL-10, IL-21, MIP-1α, MIP-1β, or MIP-3α. The Spearman correlation analysis revealed strong, positive correlations among several inflammatory mediators in HC, particularly between TNF-alpha, IL-1β, IL-17A, and IL-23, forming a highly interconnected cytokine network. In contrast, CVD patients showed fewer, weaker, and distinct correlations, with new associations such as IFN-γ with IL-1β and IL-23, suggesting a disrupted inflammatory profile. Conclusions: The distinct inflammatory profile in CVD patients, characterized by altered cytokine and chemokine levels and a less coordinated cytokine network, underscores the reconfiguration of inflammatory pathways in this condition. These findings highlight potential therapeutic targets aimed at restoring immune balance and mitigating chronic inflammation in CVD.

Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks’ gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for both mother and baby. The pathogenesis of PE develops due to a dysfunctional placenta with aberrant architecture that releases factors contributing to endothelial dysfunction, an antiangiogenic state, increased oxidative stress, and maternal inflammatory responses. Previous studies have shown a correlation between grade 3 placental calcifications and an elevated risk of developing PE at term. However, little is known about the molecular pathways leading to placental calcification. In this work, we studied the gene and protein expression of c-Jun N-terminal kinase (JNK), Runt-related transcription factor 2 (RUNX2), osteocalcin (OSC), osteopontin (OSP), pigment epithelium-derived factor (PEDF), MSX-2/HOX8, SOX-9, WNT-1, and β-catenin in placental tissue from women with late-onset PE (LO-PE). In addition, we employed von Kossa staining to detect mineral deposits in placental tissues. Our results show a significant increase of all these components in placentas from women with LO-PE. Therefore, our study suggests that LO-PE may be associated with the activation of molecular pathways of placental calcification. These results could be the starting point for future research to describe the molecular mechanisms that promote placental calcification in PE and the development of therapeutic strategies directed against it.

El síndrome hemofagocítico o linfohistiocitosis hemofagocítica es un síndrome grave de activación inmunitaria excesiva. Es muy infrecuente la asociación de síndrome hemofagocítico con infección por Mycobacterium tuberculosis. Se presenta un caso de linfohistiocitosis hemofagocítica con pancitopenia grave secundario a tuberculosis miliar en una mujer de 62 años. Durante el tratamiento antituberculoso se evidenció un empeoramiento radiológico en relación con un síndrome inflamatorio de reconstitución inmunológica. Este caso pone de manifiesto la importancia de considerar la tuberculosis como posible causa subyacente de síndrome hematofagocítico y, si se sospecha, debe iniciarse precozmente la terapia antituberculosa, incluso en ausencia de un diagnóstico definitivo.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan–Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression.

Chronic venous disease (CVD) comprises a spectrum of morphofunctional disorders affecting the venous system, affecting approximately 1 in 3 women during gestation. Emerging evidence highlights diverse maternofetal implications stemming from CVD, particularly impacting the placenta. While systemic inflammation has been associated with pregnancy-related CVD, preliminary findings suggest a potential link between this condition and exacerbated inflammation in the placental tissue. Inflammasomes are major orchestrators of immune responses and inflammation in different organs and systems. Notwithstanding the relevance of inflammasomes, specifically the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)- which has been demonstrated in the placentas of women with different obstetric complications, the precise involvement of this component in the placentas of women with CVD remains to be explored. This study employs immunohistochemistry and real-time PCR (RT-qPCR) to examine the gene and protein expression of key components in both canonical and non-canonical pathways of the NLRP3 inflammasome (NLRP3, ASC—apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain—caspase 1, caspase 5, caspase 8, and interleukin 1β) within the placental tissue of women affected by CVD. Our findings reveal a substantial upregulation of these components in CVD-affected placentas, indicating a potential pathophysiological role of the NLRP3 inflammasome in the development of this condition. Subsequent investigations should focus on assessing translational interventions addressing this dysregulation in affected patient populations.