Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries.

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.

Utero-ovarian transposition before pelvic radiation in a patient with rectal cancer: a case report and systemic literature review.

Objective: To describe a case of utero-ovarian transposition (UOT) before pelvic radiation in a patient with rectal cancer and provide a systematic literature review on all reported cases of UOT. Methods: We performed a prospective collection and revision of clinical, intraoperative, and postoperative data from a patient who underwent UOT. In addition, a systematic review of the literature available to date on all cases of UOT was realized, and 14 patients from 10 articles were included. Results: We reported the case of a 28-year-old nulligravida patient who was diagnosed with a low-grade rectal adenocarcinoma and underwent neoadjuvant chemoradiotherapy, followed by transanal total mesorectal excision (TaTME). Before starting neoadjuvant oncological therapies, the patient underwent laparoscopic UOT. The intervention was performed without complications, and the patient received neoadjuvant oncological treatments as planned. TaTME and uterus repositioning were completed six weeks after the end of radiotherapy. No complications were observed during the first 9 postoperative months. Adequate utero-ovarian perfusion was assessed by Doppler ultrasound, cervicovaginal anastomosis appeared to have healed correctly, and the patient experienced menstrual bleeding. Data from the literature review of all reported cases of UOT were presented and discussed. Conclusions: UOT represents a valuable option to preserve fertility in patients requiring pelvic radiotherapy. This study provides additional evidence on the feasibility and safety of performing UOT.

SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis.

PURPOSE: Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. METHODS: Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. RESULTS: By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. CONCLUSIONS: SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.

Transcriptional Stress Induces the Generation of DoGs in Cancer Cells.

A characteristic of the cellular response to stress is the production of RNAs generated from a readthrough transcription of genes, called downstream-of-gene-(DoG)-containing transcripts. Additionally, transcription inhibitor drugs are candidates for fighting cancer. In this work, we report the results of a bioinformatic analysis showing that one of the responses to transcription inhibition is the generation of DoGs in cancer cells. Although some genes that form DoGs were shared between the two cancer lines, there did not appear to be a functional correlation between them. However, our findings show that DoGs are generated as part of the cellular response to transcription inhibition like other types of cellular stress, suggesting that they may be part of the defense against transcriptional stress.

The M-Point A Novel Landmark in Middle Fossa Surgery: A Cadaveric Morphometric Study.

BACKGROUND: The arcuate eminence (AE) is an anatomically consistent bony protrusion located on the upper surface of the petrous bone that has been previously studied as a reference for lateral skull base approaches. There is a paucity of information in the neurosurgical literature seeking to improve the safety of the extended middle cranial fossa (MCF) approach using detailed morphometric analysis of the AE. OBJECTIVE: To evaluate the use of the AE as an anatomical landmark to help with early identification of the internal acoustic canal (IAC) in MCF approaches by means of a cadaveric study, using a new morphometric reference termed the "M-point." METHODS: A total of 40 dry temporal bones and 2 formalin-preserved, latex-injected cadaveric heads were used. The M-point was established as a new anatomic reference by identifying the intersection of a line perpendicular to the alignment of the petrous ridge (PR), originating from the midpoint of the AE, with the PR itself. Subsequent anatomical measurements were performed to measure the distance between M-point and IAC. Additional distances, including PR length and the anteroposterior and lateral AE surfaces, were also measured. RESULTS: The mean distance between the M-point and the center of the IAC was 14.9 mm (SD ± 2.09), offering a safe drilling area during an MCF approach. CONCLUSIONS: This study provides novel information on identification of a new anatomic reference point known as the M-point that that can be used to improve early surgical identification of the IAC.

Recent Advances in Understanding the Mechanistic Role of Transient Receptor Potential Ion Channels in Patients With Hypertension.

The transient receptor potential (TRP) channel superfamily is a group of nonselective cation channels that function as cellular sensors for a wide range of physical, chemical, and environmental stimuli. According to sequence homology, TRP channels are categorized into 6 subfamilies: TRP canonical, TRP vanilloid, TRP melastatin, TRP ankyrin, TRP mucolipin, and TRP polycystin. They are widely expressed in different cell types and tissues and have essential roles in various physiological and pathological processes by regulating the concentration of ions (Ca2+, Mg2+, Na+, and K+) and influencing intracellular signalling pathways. Human data and experimental models indicate the importance of TRP channels in vascular homeostasis and hypertension. Furthermore, TRP channels have emerged as key players in oxidative stress and inflammation, important in the pathophysiology of cardiovascular diseases, including hypertension. In this review, we present an overview of the TRP channels with a focus on their role in hypertension. In particular, we highlight mechanisms activated by TRP channels in vascular smooth muscle and endothelial cells and discuss their contribution to processes underlying vascular dysfunction in hypertension.

Synthesis and Characterization of Environmentally Friendly Chitosan-Arabic Gum Nanoparticles for Encapsulation of Oregano Essential Oil in Pickering Emulsion.

The encapsulation of bioactive agents through the utilization of biodegradable nanoparticles is a topic of considerable scientific interest. In this study, microcapsules composed of chitosan (CS) and Arabic gum (GA) nanoparticles were synthesized, encapsulating oregano essential oil (OEO) through Pickering emulsions and subsequent spray drying. The optimization of hybrid chitosan and Arabic gum (CS-GA) nanoparticle formation was carried out via complex coacervation, followed by an assessment of their behavior during the formation of the emulsion. Measurements of the size, contact angle, and interfacial tension of the formed complexes were conducted to facilitate the development of Pickering emulsions for encapsulating the oil under the most favorable conditions. The chitosan-Arabic gum capsules were physically characterized using scanning electron microscopy and fitted to the Beerkan estimation of soil transfer (BEST) model to determine their size distribution. Finally, the OEO encapsulation efficiency was also determined. The optimum scenario was achieved with the CS-GA 1-2 capsules at a concentration of 2% wt, featuring a contact angle of 89.1 degrees, which is ideal for the formation of oil/water (O/W) emulsions. Capsules of approximately 2.5 µm were obtained, accompanied by an encapsulation efficiency of approximately 60%. In addition, the hybrid nanoparticles that were obtained showed high biodegradability. The data within our study will contribute fundamental insights into CS-GA nanoparticles, and the quantitatively analyzed outcomes presented in this study will hold utility for forthcoming applications in environmentally friendly detergent formulations.

Oxidative Stress and Endoplasmic Reticular Stress Interplay in the Vasculopathy of Hypertension.

Under physiologic conditions, reactive oxygen species (ROS) function as signalling molecules that control cell function. However, in pathologic conditions, increased generation of ROS triggers oxidative stress, which plays a role in vascular changes associated with hypertension, including endothelial dysfunction, vascular reactivity, and arterial remodelling (termed the vasculopathy of hypertension). The major source of ROS in the vascular system is NADPH oxidase (NOX). Increased NOX activity drives vascular oxidative stress in hypertension. Molecular mechanisms underlying vascular damage in hypertension include activation of redox-sensitive signalling pathways, post-translational modification of proteins, and oxidative damage of DNA and cytoplasmic proteins. In addition, oxidative stress leads to accumulation of proteins in the endoplasmic reticulum (ER) (termed ER stress), with consequent activation of the unfolded protein response (UPR). ER stress is emerging as a potential player in hypertension as abnormal protein folding in the ER leads to oxidative stress and dysregulated activation of the UPR promotes inflammation and injury in vascular and cardiac cells. In addition, the ER engages in crosstalk with exogenous sources of ROS, such as mitochondria and NOX, which can amplify redox processes. Here we provide an update of the role of ROS and NOX in hypertension and discuss novel concepts on the interplay between oxidative stress and ER stress.

SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication.

COVID-19, caused by SARS-CoV-2, is a respiratory disease associated with inflammation and endotheliitis. Mechanisms underling inflammatory processes are unclear, but angiotensin converting enzyme 2 (ACE2), the receptor which binds the spike protein of SARS-CoV-2 may be important. Here we investigated whether spike protein binding to ACE2 induces inflammation in endothelial cells and determined the role of ACE2 in this process. Human endothelial cells were exposed to SARS-CoV-2 spike protein, S1 subunit (rS1p) and pro-inflammatory signaling and inflammatory mediators assessed. ACE2 was modulated pharmacologically and by siRNA. Endothelial cells were also exposed to SARS-CoV-2. rSP1 increased production of IL-6, MCP-1, ICAM-1 and PAI-1, and induced NFkB activation via ACE2 in endothelial cells. rS1p increased microparticle formation, a functional marker of endothelial injury. ACE2 interacting proteins involved in inflammation and RNA biology were identified in rS1p-treated cells. Neither ACE2 expression nor ACE2 enzymatic function were affected by rSP1. Endothelial cells exposed to SARS-CoV-2 virus did not exhibit viral replication. We demonstrate that rSP1 induces endothelial inflammation via ACE2 through processes that are independent of ACE2 enzymatic activity and viral replication. We define a novel role for ACE2 in COVID-19- associated endotheliitis.

Study on the types of abuse in young couples as a function of sex.

This study analyses the types of violence that can occur in intimate partner relationships among young people and their self-perception of abuse. For this purpose, we have used a survey-type methodology, with a quantitative approach. Participants were selected by means of non-probabilistic convenience and consisted of students enrolled in different degree and postgraduate courses in the Faculty of Education Sciences of the University of Granada (Spain). The sample consisted of 323 students, with a mean age of 23.8 years (SD = 5.2). Statistical and inferential tests were carried out with the data obtained using the SPSS V26 data analysis programme. The results show that the type of maltreatment most suffered, at some time by the sample participants, is emotional maltreatment, physical maltreatment, and psychological maltreatment. By comparing the means obtained, we can conclude that sex did not influence the violence suffered by young couples, which gives it a bidirectional character.

Impact of Environmental Factors on Hypertension and Associated Cardiovascular Disease.

Hypertension is the primary cause of cardiovascular diseases and is responsible for nearly 9 million deaths worldwide annually. Increasing evidence indicates that in addition to pathophysiologic processes, numerous environmental factors, such as geographic location, lifestyle choices, socioeconomic status, and cultural practices, influence the risk, progression, and severity of hypertension, even in the absence of genetic risk factors. In this review, we discuss the impact of some environmental determinants on hypertension. We focus on clinical data from large population studies and discuss some potential molecular and cellular mechanisms. We highlight how these environmental determinants are interconnected, as small changes in one factor might affect others, and further affect cardiovascular health. In addition, we discuss the crucial impact of socioeconomic factors and how these determinants influence diverse communities with economic disparities. Finally, we address opportunities and challenges for new research to address gaps in knowledge on understanding molecular mechanisms whereby environmental factors influence development of hypertension and associated cardiovascular disease.

Epiisopiloturine, an Alkaloid from Pilocarpus microphyllus, Attenuates LPS-Induced Neuroinflammation by Interfering in the TLR4/NF-κB-MAPK Signaling Pathway in Microglial Cells.

Neuroinflammation is present in the pathophysiological mechanisms of several diseases that affect the central nervous system (CNS). Microglia have a prominent role in initiating and sustaining the inflammatory process. Epiisopiloturine (EPI) is an imidazole alkaloid obtained as a by-product of pilocarpine extracted from Pilocarpus microphyllus (jaborandi) and has shown promising anti-inflammatory and antinociceptive properties. In the present study, we investigated the effects of EPI on the inflammatory response in microglial cells (BV-2 cells) induced by lipopolysaccharide (LPS) and explored putative underlying molecular mechanisms. Cell viability was not affected by EPI (1-100 µg/mL) as assessed by both LDH activity and the MTT test. Pretreatment with EPI (25, 50, and 100 µg/mL) significantly reduced the proinflammatory response induced by LPS, as observed by a decrease in nitrite oxide production and iNOS protein expression. EPI (25 µg/mL) reduced IL-6 and TNF-α production, by 40% and 34%, respectively. However, no changes were observed in the anti-inflammatory IL-10 production. Mechanistically, EPI inhibited the TLR4 expression and phosphorylation of NF-κB p65 and MAPKs (JNK and ERK1/2) induced by LPS, but no changes were observed in TREM2 receptor expression in LPS-stimulated cells. In conclusion, our data demonstrated the potent anti-inflammatory properties of EPI in microglial cells. These effects are associated with the reduction of TLR4 expression and inhibition of intracellular signaling cascades, including NF-κB and MAPKs (JNK and ERK1/2).

Antagonistic Toxic Effects of Surfactants Mixtures to Bacteria Pseudomonas putida and Marine Microalgae Phaeodactylum tricornutum.

Surfactants can be found in an ever-widening variety of products and applications, in which the combination of several types of surfactants is used to reinforce their properties, looking for synergistic effects between them. After use, they tend to be discarded into wastewater, ending up in aquatic bodies with concerning harmful and toxic effects. The aim of this study is the toxicological assessment of three anionic surfactants (ether carboxylic derivative, EC) and three amphoteric surfactants (amine-oxide-based, AO), individually and in binary mixtures of them (1:1 w/w), to bacteria Pseudomonas putida and marine microalgae Phaeodactylum tricornutum. Critical Micelle Concentration (CMC) was determined to demonstrate the capacity to reduce surface tension and the toxicity of the surfactants and mixtures. Zeta potential (ζ-potential) and micelle diameter (MD) were also determined to confirm the formation of mixed surfactant micelles. The Model of Toxic Units (MTUs) was used to quantify the interactions of surfactants in binary mixtures and to predict if the concentration addition or response addition principle can be assumed for each mixture. The results showed a higher sensitivity of microalgae P. tricornutum to the surfactants tested and their mixtures than bacteria P. putida. Antagonism toxic effects have been detected in the mixture of EC + AO and in one binary mixture of different AOs; this is to say, the mixtures showed lower toxicity than expected.

Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

CONTEXT: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. OBJECTIVE: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. METHODS: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. RESULTS: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. CONCLUSION: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Overexpression of Physcomitrium patens cell cycle regulators leads to larger gametophytes.

Regulation of cell division is crucial for the development of multicellular organisms, and in plants, this is in part regulated by the D-type cyclins (CYCD) and cyclin-dependent kinase A (CDKA) complex. Cell division regulation in Physcomitrium differs from other plants, by having cell division checks at both the G1 to S and G2 to M transition, controlled by the CYCD1/CDKA2 and CYCD2/CDKA1 complexes, respectively. This led us to hypothesize that upregulation of cell division could be archived in Bryophytes, without the devastating phenotypes observed in Arabidopsis. Overexpressing lines of PpCYCD1, PpCYCD2, PpCDKA1, or PpCDKA2 under Ubiquitin promotor control provided transcriptomic and phenotypical data that confirmed their involvement in the G1 to S or G2 to M transition control. Interestingly, combinatorial overexpression of all four genes produced plants with dominant PpCDKA2 and PpCYCD1 phenotypes and led to plants with twice as large gametophores. No detrimental phenotypes were observed in this line and two of the major carbon sinks in plants, the cell wall and starch, were unaffected by the increased growth rate. These results show that the cell cycle characteristics of P. patens can be manipulated by the ectopic expression of cell cycle regulators.

Withdrawn as duplicate: Expanding the phenotypic spectrum of Kenny-Caffey syndrome: a case series and systematic literature review.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Sex Education and Comprehensive Health Education in the Future of Educational Professionals.

This work shows an approach to comprehensive sexual education as an anthropological key to promoting health in the self-realisation of future education professionals. Comprehensive sexual education and health form a system. To carry out this study, we have analysed the opinion that students of the Faculty of Education Sciences of the University of Granada (Spain) have about the comprehensive sexual education received and the importance of this training in their professional practice. For this purpose, we used a quantitative and exploratory research design, using a questionnaire as an instrument for collecting information with a sample of 293 students. The results show that students have received poor sex education, along with the belief that education professionals do not receive proper and organised training in sex education. We can conclude that the majority of respondents consider sex education to be a recognised right, highlighting the importance of education professionals receiving proper training in sex education at university, where content related to respect, education for equality, and sexual health is prioritised. Sexuality constitutes the fundamental anthropological structure: comprehensive sexual education is a source of personal (corporal, psychic, spiritual) and social health, hence the importance of educating in comprehensive sexuality.

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7.

Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg2+ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.

Exosomes and the cardiovascular system: role in cardiovascular health and disease.

Exosomes, which are membrane-bound extracellular vesicles (EVs), are generated in the endosomal compartment of almost all eukaryotic cells. They are formed upon the fusion of multivesicular bodies and the plasma membrane and carry proteins, nucleic acids, lipids and other cellular constituents from their parent cells. Multiple factors influence their production including cell stress and injury, humoral factors, circulating toxins, and oxidative stress. They play an important role in intercellular communication, through their ability to transfer their cargo (proteins, lipids, RNAs) from one cell to another. Exosomes have been implicated in the pathophysiology of various diseases including cardiovascular disease (CVD), cancer, kidney disease, and inflammatory conditions. In addition, circulating exosomes may act as biomarkers for diagnostic and prognostic strategies for several pathological processes. In particular exosome-containing miRNAs have been suggested as biomarkers for the diagnosis and prognosis of myocardial injury, stroke and endothelial dysfunction. They may also have therapeutic potential, acting as vectors to deliver therapies in a targeted manner, such as the delivery of protective miRNAs. Transfection techniques are in development to load exosomes with desired cargo, such as proteins or miRNAs, to achieve up-regulation in the host cell or tissue. These advances in the field have the potential to assist in the detection and monitoring progress of a disease in patients during its early clinical stages, as well as targeted drug delivery.