Justin Aickareth

Background/Objectives: Cerebral cavernous malformations (CCMs) are neurological disorders that increase the risk of hemorrhagic stroke. The Mexican Hispanic population has a higher prevalence of both CCMs and metabolic syndrome (MetS), defined by the presence of three or more of the following: central obesity, elevated triglycerides, low HDL, dyslipidemia, hypertension, or elevated fasting glucose. MetS is also associated with an increased risk of hemorrhagic stroke. However, the connection between MetS and hemorrhagic stroke in Hispanic CCM patients remains uncertain. Additionally, it is unclear if Hispanic CCM patients have different cardiometabolic profiles compared to controls. Methods: We analyzed a retrospective cohort of Mexican Hispanic adult CCM patients, including age- and gender-matched controls from the NHANES database. Fisher’s exact test or an unpaired Student’s t-test was used to compare risk factors between the CCM cohort and controls. Additionally, we conducted relative risk regression analysis to assess the adjusted association of MetS with hemorrhagic stroke. Results: The CCM cohort showed higher rates of epilepsy (24.6% vs. 1.6%, p < 0.001) and hemorrhagic stroke (36.6% vs. 3.6%, p < 0.001), but a lower prevalence of MetS (14% vs. 54.8%, p < 0.001) compared to age- and gender-matched Mexican Hispanic controls. The adjusted analysis revealed that among CCM patients in the older age group (age ≥ 50 years), MetS was associated with hemorrhagic stroke (RR = 2.38, 95%CI: 1.40–4.02, p = 0.001). Conclusions: This study reveals distinct features of CCMs in the Mexican Hispanic population, indicating a higher risk of hemorrhagic stroke and epilepsy compared to other ethnic groups. To mitigate the risk of hemorrhagic stroke, controlling blood pressure and managing comorbidities like metabolic syndrome (MetS) and epilepsy are essential, particularly in CCM patients aged 50 years and above.

Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood–brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood–brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood–brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).

Progesterone (PRG) is a key cyclical reproductive hormone that has a significant impact on female organs in vertebrates. It is mainly produced by the corpus luteum of the ovaries, but can also be generated from other sources such as the adrenal cortex, Leydig cells of the testes and neuronal and glial cells. PRG has wide-ranging physiological effects, including impacts on metabolic systems, central nervous systems and reproductive systems in both genders. It was first purified as an ovarian steroid with hormonal function for pregnancy, and is known to play a role in pro-gestational proliferation during pregnancy. The main function of PRG is exerted through its binding to progesterone receptors (nPRs, mPRs/PAQRs) to evoke cellular responses through genomic or non-genomic signaling cascades. Most of the existing research on PRG focuses on classic PRG-nPR-paired actions such as nuclear transcriptional factors, but new evidence suggests that PRG also exerts a wide range of PRG actions through non-classic membrane PRG receptors, which can be divided into two sub-classes: mPRs/PAQRs and PGRMCs. The review will concentrate on recently found non-classical membrane progesterone receptors (mainly mPRs/PAQRs) and speculate their connections, utilizing the present comprehension of progesterone receptors.

It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells. However, the mechanisms responsible for zinc accumulation and the consequences of zinc dysregulation are poorly understood. In this review, we detailed cellular zinc regulation/dysregulation under the influence of varying levels of sex steroids and breast cancer tumorigenesis to try to better understand the intricate relationship between these factors based on our current understanding of the CmPn/CmP signaling network. We also made some efforts to propose a relationship between zinc signaling and the CmPn/CmP signaling network.