Morphology of human sinoatrial node and its surrounding right atrial muscle in the global obesity pandemic-does fat matter?

Introduction: The sinus node (SN) is the main pacemaker site of the heart, located in the upper right atrium at the junction of the superior vena cava and right atrium. The precise morphology of the SN in the human heart remains relatively unclear especially the SN microscopical anatomy in the hearts of aged and obese individuals. In this study, the histology of the SN with surrounding right atrial (RA) muscle was analyzed from young non-obese, aged non-obese, aged obese and young obese individuals. The impacts of aging and obesity on fibrosis, apoptosis and cellular hypertrophy were investigated in the SN and RA. Moreover, the impact of obesity on P wave morphology in ECG was also analyzed to determine the speed and conduction of the impulse generated by the SN. Methods: Human SN/RA specimens were dissected from 23 post-mortem hearts (preserved in 4% formaldehyde solution), under Polish local ethical rules. The SN/RA tissue blocks were embedded in paraffin and histologically stained with Masson's Trichrome. High and low-magnification images were taken, and analysis was done for appropriate statistical tests on Prism (GraphPad, USA). 12-lead ECGs from 14 patients under Polish local ethical rules were obtained. The P wave morphologies from lead II, lead III and lead aVF were analyzed. Results: Compared to the surrounding RA, the SN in all four groups has significantly more connective tissue (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals and young obese individuals) and significantly smaller nodal cells (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals, young obese individuals). In aging, overall, there was a significant increase in fibrosis, apoptosis, and cellular hypertrophy in the SN (P ≤ 0.05) and RA (P ≤ 0.05). Obesity did not further exacerbate fibrosis but caused a further increase in cellular hypertrophy (SN P ≤ 0.05, RA P ≤ 0.05), especially in young obese individuals. However, there was more infiltrating fat within the SN and RA bundles in obesity. Compared to the young non-obese individuals, the young obese individuals showed decreased P wave amplitude and P wave slope in aVF lead. Discussion: Aging and obesity are two risk factors for extensive fibrosis and cellular hypertrophy in SN and RA. Obesity exacerbates the morphological alterations, especially hypertrophy of nodal and atrial myocytes. These morphological alterations might lead to functional alterations and eventually cause cardiovascular diseases, such as SN dysfunction, atrial fibrillation, bradycardia, and heart failure.

The Fetal Alcohol Spectrum Disorders-An Overview of Experimental Models, Therapeutic Strategies, and Future Research Directions.

Since the establishment of a clear link between maternal alcohol consumption during pregnancy and certain birth defects, the research into the treatment of FASD has become increasingly sophisticated. The field has begun to explore the possibility of intervening at different levels, and animal studies have provided valuable insights into the pathophysiology of the disease, forming the basis for implementing potential therapies with increasingly precise mechanisms. The recent reports suggest that compounds that reduce the severity of neurodevelopmental deficits, including glial cell function and myelination, and/or target oxidative stress and inflammation may be effective in treating FASD. Our goal in writing this article was to analyze and synthesize current experimental therapeutic interventions for FASD, elucidating their potential mechanisms of action, translational relevance, and implications for clinical application. This review exclusively focuses on animal models and the interventions used in these models to outline the current direction of research. We conclude that given the complexity of the underlying mechanisms, a multifactorial approach combining nutritional supplementation, pharmacotherapy, and behavioral techniques tailored to the stage and severity of the disease may be a promising avenue for further research in humans.

Systematic-Narrative Hybrid Literature Review: Crosstalk between Gastrointestinal Renin-Angiotensin and Dopaminergic Systems in the Regulation of Intestinal Permeability by Tight Junctions.

In the first part of this article, the role of intestinal epithelial tight junctions (TJs), together with gastrointestinal dopaminergic and renin-angiotensin systems, are narratively reviewed to provide sufficient background. In the second part, the current experimental data on the interplay between gastrointestinal (GI) dopaminergic and renin-angiotensin systems in the regulation of intestinal epithelial permeability are reviewed in a systematic manner using the PRISMA methodology. Experimental data confirmed the copresence of DOPA decarboxylase (DDC) and angiotensin converting enzyme 2 (ACE2) in human and rodent enterocytes. The intestinal barrier structure and integrity can be altered by angiotensin (1-7) and dopamine (DA). Both renin-angiotensin and dopaminergic systems influence intestinal Na+/K+-ATPase activity, thus maintaining electrolyte and nutritional homeostasis. The colocalization of B0AT1 and ACE2 indicates the direct role of the renin-angiotensin system in amino acid absorption. Yet, more studies are needed to thoroughly define the structural and functional interaction between TJ-associated proteins and GI renin-angiotensin and dopaminergic systems.

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. METHODS: During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. RESULTS: The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. CONCLUSIONS: PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus-pituitary-adrenal axis overactivity.

Description and prevalence of ventricular mitral annular disjunction: variation of normality or pathological variant?

INTRODUCTION AND OBJECTIVES: The aim of this study was to investigate a new variation of the atrial wall-mitral annulus-ventricular wall junction along the mural mitral leaflet and commissures: the ventricular mitral annular disjunction (v-MAD). This new variant is characterized by spatial displacement of the mitral leaflet hinge line by more than 2mm toward the left ventricle. METHODS: We examined a cohort of autopsied human hearts (n=224, 21.9% females, 47.9±17.6 years) from patients without known cardiovascular disease to identify the presence of v-MAD. RESULTS: More than half (57.1%) of the hearts showed no signs of MAD in the mural mitral leaflet or mitral commissures. However, v-MAD was found in 23.6% of cases, located within 20.1% of mural leaflets, 2.2% in superolateral commissures, and 1.3% in inferoseptal commissures. V-MAD was not uniformly distributed along the mitral annulus circumference, with the most frequent site being the P2 scallop (19.6% of hearts). The v-MAD height was significantly greater in mural leaflets than in commissures (4.4 mm±1.2 mm vs 2.1 mm±0.1 mm; P<.001). No specific variations in mitral valve morphology or anthropometrical features of donors were associated with the presence or distribution of v-MADs. Microscopic examinations revealed the overlap of the thin layer of atrial myocardium over ventricular myocardium in areas of v-MAD. CONCLUSIONS: Our study is the first to present a detailed definition and morphometric description of v-MAD. Further studies should focus on the clinical significance of v-MAD to elucidate whether it represents a benign anatomical variant or a significant clinical anomaly.

Morphology of the mural and commissural atrioventricular junction of the mitral valve.

OBJECTIVE: This study investigates mitral annular disjunctions (MAD) in the atrial wall-mitral annulus-ventricular wall junction along the mural mitral leaflet and commissures. METHODS: We examined 224 adult human hearts (21.9% females, 47.9±17.6 years) devoid of cardiovascular diseases (especially mitral valve disease). These hearts were obtained during forensic medical autopsies conducted between January 2018 and June 2021. MAD was defined as a spatial displacement (≥2 mm) of the leaflet hinge line towards the left atrium. We provided a detailed morphometric analysis (disjunction height) and histological examination of MADs. RESULTS: MADs were observed in 19.6% of all studied hearts. They appeared in 12.1% of mural leaflets. The P1 scallop was the primary site for disjunctions (8.9%), followed by the P2 scallop (5.4%) and P3 scallop (4.5%). MADs were found in 9.8% of all superolateral and 5.8% of all inferoseptal commissures. The average height for leaflet MADs was 3.0±0.6 mm, whereas that for commissural MADs was 2.1±0.5 mm (p<0.0001). The microscopical arrangement of MADs in both the mural leaflet and commissures revealed a disjunction shifted towards left atrial aspect, filled with connective tissue and covered by elongated valve annulus. The size of the MAD remained remarkably uniform and showed no correlation with other anthropometric factors (all p>0.05). CONCLUSIONS: In the cohort of the patients with healthy hearts, MAD is present in about 20% of all studied hearts. The MADs identified tend to be localised, confined to a single scallop. Moreover, MADs in the commissures are notably smaller than those in the mural leaflet.

Low-frequency electromagnetic fields influence the expression of calcium metabolism related proteins in leukocytic cell lines.

Our study aimed to verify the hypothesis concerning low-frequency magnetic fields (LF-MFs)-related changes in cell viability through the biomechanism(s) based on calcineurin (CaN)-mediated signaling pathways triggered via ROS-like molecules. For experiments, Mono Mac 6 and U937 leukocytic cell lines were chosen and exposed to various LF-MFs and/or puromycin (PMC). The protein expression level of key regulatory proteins of calcium metabolism was examined by Western Blot analysis. In turn, the reactive oxygen species (ROS) and cell viability parameters were evaluated by cytochrome C reduction assay and flow cytometry, respectively. The simultaneous action of applied MF and PMC influenced cell viability in a MF-dependent manner. The changes in cell viability were correlated with protein expression and ROS levels. It was verified experimentally that applied stress stimuli influence cell susceptibility to undergo cell death. Moreover, the evoked bioeffects might be recognized as specific to both types of leukocyte populations.

Neuroprotective Activity of Enantiomers of Salsolinol and N-Methyl-(R)-salsolinol: In Vitro and In Silico Studies.

Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that R and S enantiomers of salsolinol, which we purified from commercially available racemic mixture by means of high-performance liquid chromatography, exhibited neuroprotective properties (at the concentration of 50 µM) toward the human dopaminergic SH-SY5Y neuroblastoma cell line. Furthermore, within the study, we observed no toxic effect of N-methyl-(R)-salsolinol on SH-SY5Y neuroblastoma cells up to the concentration of 750 µM, either. Additionally, our molecular docking analysis showed that enantiomers of salsolinol should exhibit a distinct ability to interact with dopamine D2 receptors. Thus, we postulate that our results highlight the need to acknowledge salsolinol as an active dopamine metabolite and to further explore the neuroregulatory role of enantiomers of salsolinol.

Expanded insights into the neural component of the activity-based anorexia animal model - morphological changes in the enteric nervous system and altered pain perception.

Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunction in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assessment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have significantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.

Postprandial effect of gastrointestinal hormones and gastric activity in patients with irritable bowel syndrome.

Altered gut regulation, including motor and secretory mechanisms, is characteristic of irritable bowel syndrome (IBS). The severity of postprandial symptoms in IBS patients is associated with discomfort and pain; gas-related symptoms such as bloating and abdominal distension; and abnormal colonic motility. The aim of this study was to assess the postprandial response, i.e., gut peptide secretion and gastric myoelectric activity, in patients with constipation-predominant IBS. The study was conducted on 42 IBS patients (14 males, 28 females, mean age 45.1 ± 15.3 years) and 42 healthy participants (16 males, 26 females, mean age 41.1 ± 8.7 years). The study assessed plasma gut peptide levels (gastrin, CCK-Cholecystokinin, VIP-Vasoactive Intestinal Peptide, ghrelin, insulin) and gastric myoelectric activity obtained from electrogastrography (EGG) in the preprandial and postprandial period (meal-oral nutritional supplement 300 kcal/300 ml). Mean preprandial gastrin and insulin levels were significantly elevated in IBS patients compared to the control group (gastrin: 72.27 ± 26.89 vs. 12.27 ± 4.91 pg/ml; p < 0.00001 and insulin: 15.31 ± 12.92 vs. 8.04 ± 3.21 IU/ml; p = 0.0001), while VIP and ghrelin levels were decreased in IBS patients (VIP: 6.69 ± 4.68 vs. 27.26 ± 21.51 ng/ml; p = 0.0001 and ghrelin: 176.01 ± 88.47 vs. 250.24 ± 84.55 pg/ml; p < 0.0001). A nonsignificant change in the CCK level was observed. IBS patients showed significant changes in postprandial hormone levels compared to the preprandial state-specifically, there were increases in gastrin (p = 0.000), CCK (p < 0.0001), VIP (p < 0.0001), ghrelin (p = 0.000) and insulin (p < 0.0001). Patients with IBS showed reduced preprandial and postprandial normogastria (59.8 ± 22.0 vs. 66.3 ± 20.2%) compared to control values (83.19 ± 16.7%; p < 0.0001 vs. 86.1 ± 9.4%; p < 0.0001). In response to the meal, we did not observe an increase in the percentage of normogastria or the average percentage slow-wave coupling (APSWC) in IBS patients. The postprandial to preprandial power ratio (PR) indicates alterations in gastric contractions; in controls, PR = 2.7, whereas in IBS patients, PR = 1.7, which was significantly lower (p = 0.00009). This ratio reflects a decrease in gastric contractility. Disturbances in the postprandial concentration of gut peptides (gastrin, insulin and ghrelin) in plasma may contribute to abnormal gastric function and consequently intestinal motility, which are manifested in the intensification of clinical symptoms, such as visceral hypersensitivity or irregular bowel movements in IBS patients.

Salsolinol Protects SH-SY5Y Cells Against MPP+ Damage and Increases Enteric S100-Immunoreactivity in Wistar Rats.

A dopamine derivative, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, known as salsolinol (SAL), has increasingly gained attention since its first detection in the urine of Parkinson's disease patients treated with levodopa, and has been proposed as a possible neurotoxic contributor to the disease. Yet, so far, the neurobiological role of SAL remains unclear. Thus, the main aims of our study were to compare the neurotoxic potential of SAL with MPP+ (1-methyl-4-phenylpyridinium ion) in vitro, and to examine intestinal and metabolic alterations following intraperitoneal SAL administration in vivo. In vitro, SH-SY5Y neuroblastoma cell line was monitored following MPP+ and SAL treatment. In vivo, Wistar rats were subjected to SAL administration by either osmotic intraperitoneal mini-pumps or a single intraperitoneal injection, and after two weeks, biochemical and morphological parameters were assessed. SH-SY5Y cells treated with MPP+ (1000 µM) and SAL (50 µM) showed increase in cell viability and fluorescence intensity in comparison with the cells treated with MPP+ alone. In vivo, we predominantly observed decreased collagen content in the submucosal layer, decreased neuronal density with comparable ganglionic area in the jejunal myenteric plexus, and increased glial S100 expression in both enteric plexuses, yet with no obvious signs of inflammation. Besides, glucose and triglycerides levels were lower after single SAL-treatment (200 mg/kg), and low- to high-density lipoprotein (LDL/HDL) ratio and aspartate to alanine aminotransferases (AST/ALT) ratio levels were higher after continuous SAL-treatment (200 mg/kg in total over 2 weeks). Low doses of SAL were non-toxic and exhibited pronounced neuroprotective properties against MPP+ in SH-SY5Y cell line, which supports the use of SAL as a reference compound for in vitro studies. In vivo results give insight into our understanding of gastrointestinal remodeling following intraperitoneal SAL administration, and might represent morphological correlates of a microglial-related enteric neurodegeneration and dopaminergic dysregulation.

The autonomic nervous system in anorexia nervosa - an implication for the fat tissue.

Eating disorders are a heterogeneous group of diseases affecting mainly young people in developed countries. Among them, anorexia nervosa (AN) is the one with the highest mortality, up to five times higher compared to healthy individuals. The etiology of this medical condition is complex and still un- certain. However, disturbances of the autonomic nervous system (ANS) and increased lipolysis resulting in a decrease of the adipose tissue volume are common findings among AN patients. Since ANS is directly connected to adipocyte tissue, thus significantly affecting the body's metabolic homeostasis, we suspect that this relationship may be a potential pathophysiological underpinning for the development of AN. In this narrative review, we have analyzed scientific reports on ANS activity in AN considering different phases of the disease in humans as well as animal models. Due to the different effects of the disease itself on the ANS as well as specific variations within animal models, the common feature seems to be dysregulation of its function without the identification of one universal pattern. Nonetheless, higher norepinephrine concentrations have been reported in adipocyte tissue, suggesting local dominance of the sym- pathetic nervous system. Further studies should explore in depth the modulation of sympathetic in adipose tissue factor and help answer key questions that arise during this brief narrative review.

Differences in the cardiovascular hemodynamic response between the Valsalva and Reverse Valsalva Maneuvers in healthy subjects.

BACKGROUND: The Valsalva Maneuver (VM) is the first-line treatment for paroxysmal supraventricular tachycardia, but a recent, novel, and efficient tool to restore sinus rhythm has been described, i.e., the Reverse Valsalva (RV). This study aims to compare changes in cardiovascular hemodynamics and autonomic system activity (ANS) based on heart rate variability (HRV) analysis during both maneuvers. METHODS: Fifteen healthy participants performed the VM and RV maneuvers three times in a sitting position for durations of 15 s and 10 s, respectively. Blood pressure (BP) and heart rate (HR) were continuously monitored before, during and after the tests. Autonomic system activity was evaluated using frequency-domain analysis of HRV. RESULTS: The decrease in HR from baseline to the lowest values, expressed as a ratio, was similar during both maneuvers (0.81 during the RV vs. 0.79 during the VM, p = 0.27). However, the final lowest HR in response to the RV was higher than that in response to the VM, 70/min vs. 59/min (p <0.001). The activation of the autonomic nervous system during the most bradycardic phase of the RV (phase II) and VM (phase IV) showed that the total power of HRV was less prominent during the RV than during the VM (p <0.012), with similar levels of parasympathetic activation. CONCLUSIONS: Our results showed less HR slowdown during the RV than during the VM. The changes in HRV parameters during both procedures in particular phases of the RV and VM suggest that the autonomic nervous system is activated alternately, so these tests can be used complementarily in a clinical setting with different results.

The influence of 5-fluorouracil on the α-ketoglutarate dehydrogenase complex in rat's cardiac muscle - a preliminary study.

5-fluorouracil (5-FU), which is a commonly used chemotherapy agent exerts undesired cardiac toxicity. Mitochondrial dysfunction is thought to be one of potentially important mechanisms of 5-FU- induced cardiotoxicity. α-ketoglutarate dehydrogenase (α-KGDHC) is the key regulatory enzyme of TCA cycle. The complex consists of multiple copies of three catalytic subunits: α-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). α-KGDHC together with branched chain α-ketoacid dehydrogenase (BCKDH) and pyruvate dehydrogenase (PDH), are the members of 2-oxoacid dehydrogenases family that share some structural and functional similarities. Recently, it has been found that 5-FU stimulates BCKDH in rat's cardiac muscle. Therefore, we hypothesize that 5-FU modifies α-KGDHC activity and affects cardiac muscle metabolism. The aim of this study was to determine the effect of 5-FU on α-KGDHC activity and protein levels of E1 and E2 subunits of the complex in rat's cardiac muscle. Wistar male rats were administered with 4 doses of 5-FU, 150 mg/ kg b.wt. each (study group) or 0.3% methylcellulose (control group). α-KGDHC activity was assayed spectrophotometrically. The E1 and E2 proteins levels were quantified by Western blot. 5-FU administration resulted in stimulation of myocardial α-KGDHC activity in rats. In addition, E2 protein level increased in response to 5-FU treatment, while the E1 protein level remained unchanged. Up-regulation of α-KGDHC appears to result from change in E2 subunit protein level. However, the effect of 5-FU on factors modifying α-KGDHC activity at post-translational level cannot be excluded.

The Inhibitory Effect of Human Plasma Albumin and Haptoglobin on Platelet Aggregation and 5-HT Release.

Platelet aggregation contributes to the pathogenesis of cardiovascular diseases. After activation it leads to dense granule secretion and 5-HT release. The question arises; how platelet aggregation is endogenously controlled during blood circulation. In preliminary studies, we observed that human platelets aggregate more rapidly when suspended in buffer as compared to those suspended in plasma (PRP). These observations point to the presence of an endogenous substance that may inhibit arachidonic acid- induced platelet aggregation. An analysis of plasma Cohn fractions demonstrated that most of the plasma inhibitory activity was associated with albumin-rich and α-globulin rich protein fractions. The identity of plasma endogenous inhibitors of platelet aggregation (EIPA) was established by affinity chromatography on Cibacron Blue F3G-A for specific removal of albumin. The association of α-globulins to EIPA activity was recognized as due to haptoglobin by affinity chromatography on a column of hemoglobin-sepharose. In addition, we also found that the distribution of EIPA activity varies according to sex and physiological state. These findings reveal that EIPA may act by modulation of arachidonic acid metabolism or sequestering the fatty acid substrate.

Modulating the activity of fluoropyrimidines against colorectal cancer by Vitamin D and its analogs.

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second most deadly cancer. Scientists have projected that by 2040, the prevalence will reach up to 3.2 million new cases annually due to population aging, disadvantageous diet transformations, and elevated exposure to risk factors. In the past decades, the five-year survival rate in colorectal cancer has significantly increased to 65% due to the development of an early endoscopic diagnosis and new chemotherapeutic approaches. Fluoropyrimidines, such as 5-fluorouracil or capecitabine, are commonly used to treat CRC. One of the most fundamental mechanisms of 5-FU is based on the inhibition of thymidylate synthase. This action is responsible for the therapeutic, but also toxic, effects of the drug. In this short review, we discuss the possible effects of vitamin D activity on colorectal cancer cells in relation to fluoropyrimidines. PubMed, Embase, and Web of Science databases were searched up to January 2022 for studies on vitamin D and 5-fluorouracil interaction mechanisms. Original studies, case reports, and review articles were included. Vitamin D or its analogs target multiple biochemical pathways and modulate numerous pathophysiological mechanisms in the course of colon cancer, including those related to the pharmacological sites of fluoropyrimidines. However, the available data concerning vitamin D-fluoropyrimidine pharmacological interactions are limited, especially regarding patients suffering from colon cancer and being treated with fluoropyrimidines.s.

Identification of PDGFRα+ cells in uterine fibroids - link between angiogenesis and uterine telocytes.

Introduction: Telocytes (TCs), also called interstitial Cajal-like cells (ICLC), CD34+ cells or PDGFRα+ cells (platelet-derived growth factor receptor α positive cells), a new type of cell of mesenchymal origin, were described over one decade ago. The unique nature of these cells still deserves attention from the scientific community. Telocytes make homo- and heterocellular contact with myocytes, immunocytes and nerves, have their own immunohistochemical and secretome profiles and thus might regulate local regenerative processes including angiogenesis and fibrosis. The aim of our study was to observe the missing link between angiogenesis and telocytes in leiomyoma, the most common benign tumors affecting women of reproductive age. Material and methods: We observed uterine tissue samples from leiomyoma, adjacent myometrium and unchanged tissue from patients with leiomyoma and control subjects using routine histology, histochemistry, immunofluorescence (CD117, CD31, CD34, PDGFRα, tryptase, sFlt-1) and image analysis methods. Results: The decline of the telocyte density in the foci of fibroids correlated with poor vascularization inside the leiomyoma. Moreover, the expression of sFlt-1 (anti-angiogenic-related factor) significantly increased inside a fibroid. In leiomyoma the decrease of telocyte and blood micro-vessel density was accompanied by prevalence of collagen deposits, unlike the unchanged myometrium. Conclusions: Our results demonstrate TCs in human uterine fibroids and highlight their possible involvement in the pathogenesis of myometrial pathology in the context of angiogenesis.

Protein expression changes during phagocytosis influenced by low-frequency electromagnetic field exposure.

The aim of our studies was to determine the influence of a low-frequency electromagnetic field (EMF) on the phagocytosis of latex beads (LBs) and the expression level of proteins/genes in the human monocytic macrophage Mono Mac 6 (MM6) cell line in in vitro conditions. Before phagocytosis assay cells were pre-stimulated with infectious agents such as lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB), or the proliferatory agent phytohaemagglutinin (PHA), and then exposed to EMF (30 mT, 7 Hz, 3 h). The expression of cytoplasmic proteins like iPLA, cPLA, iNOS, NLR3/4, and Hsp70 involved in the immune response pathways to phagocytosed particles were evaluated with the usage of the Western blot analysis. mRNA encoding the iNOS protein was detected by reverse transcription PCR method. The most meaningful changes were observed for PLA2 and NLC4 proteins level and between iNOS protein expression and mRNA encoding iNOS protein amount. The EMF exposure exerted the strongest effect on iNOS encoding mRNA in cells pre-stimulated with LPS or SEB and phagocytosing LBs. The influence of EMF on phagocytosis was experimentally proved for the first time and there is a need for further investigations in term of the usage of EMF as a prospect, supportive therapy.

Oviductal Oxygen Homeostasis in Patients with Uterine Myoma: Correlation between Hypoxia and Telocytes.

Oxygen balance is crucial for angiogenesis, immunity, and tissue repair. The human oviduct is essential for reproductive function, and any imbalance in homeostasis leads to fertility disturbances and might be a reason for ectopic pregnancy development. Uterine myoma is a widespread benign tumour, which is often accompanied by infertility. Telocytes have been discussed in the contexts of motility, fibrosis development, and angiogenesis. We observed the oviducts from patients with and without uterine myoma, comparing the expression of HIF-1, HO, VEGF and its receptor, NOS, oestrogen, and progesterone receptors by immunolabeling. The myometrial and oviductal telocytes were also compared in both groups. Biochemical analyses were conducted for FSH, LH, AMH, sFlt, oestrogen, and progesterone in blood samples. Patients with uterine myoma have different expressions of sex steroid receptors and an increased number of telocytes. The decreasing VEFG expression was compensated by the rise in the HIF-1 and NOS expression. Blood biochemical analyses revealed a higher progesterone level and lower AMH in patients with uterine myoma. No differences in sFlt, FSH, and LF were observed. Uterine myoma impacts oviduct oxygen homeostasis and might cause fertility disturbances (uterine and oviductal infertility factors).