Effects of Gender and Vitamin D on Vascular Reactivity of the Carotid Artery on a Testosterone-Induced PCOS Model.

The negative cardiovascular effects of polycystic ovary syndrome (PCOS) and vitamin D deficiency (VDD) have been discussed previously; however, the sex differences between PCOS females and males are not yet known. Our aim was to investigate the effect of PCOS and VDD in the carotid artery of male and female Wistar rats. Females were treated with transdermal testosterone (Androgel) for 8 weeks, which caused PCOS. VDD and vitamin D supplementation were accomplished via diet. The carotid arteries' contraction and relaxation were examined using myography. Receptor density was investigated using immunohistochemistry. In PCOS females, angiotensin receptor density, angiotensin II-induced contraction, androgen receptor optical density, and testosterone-induced relaxation increased. The increased contractile response may increase cardiovascular vulnerability in women with PCOS. As an effect of VDD, estrogen receptor density increased in all our groups, which probably compensated for the reduced relaxation caused by VDD. Testosterone-induced relaxation was decreased as a result of VDD in males and non-PCOS females, whereas this reduction was absent in PCOS females. Male sex is associated with increased contraction ability compared with non-PCOS and PCOS females. VDD and Androgel treatment show significant gender differences in their effects on carotid artery reactivity. Both VDD and PCOS result in a dysfunctional vascular response, which can contribute to cardiovascular diseases.

Structural Features of Small Molecule Antioxidants and Strategic Modifications to Improve Potential Bioactivity.

This review surveys the major structural features in various groups of small molecules that are considered to be antioxidants, including natural and synthetic compounds alike. Recent advances in the strategic modification of known small molecule antioxidants are also described. The highlight is placed on changing major physicochemical parameters, including log p, bond dissociation energy, ionization potential, and others which result in improved antioxidant activity.

Sex differences in rat renal arterial responses following exercise training.

During aerobic exercise, hemodynamic alterations occur. Although blood flow in skeletal muscle arteries increases, it decreases in visceral vessels because of mesenterial vasoconstriction. However, maintaining renal blood flow during intensive sport is also a priority. Our aim was to investigate the changes of vascular reactivity and histology of isolated renal artery of male and female rats in response to swim training. Wistar rats were distributed into four groups: male sedentary (MSed), male trained (MTr), female sedentary (FSed), and female trained (FTr). Trained animals underwent a 12-wk-long intensive swimming program. Vascular function of isolated renal artery segments was examined by wire myography. Phenylephrine-induced contraction was lower in FSed than in MSed animals, and it was decreased by training in male but not in female animals. Inhibition of cyclooxygenases by indomethacin reduced contraction in both sedentary groups, and in MTr but not in FTr animals. Inhibition of nitric oxide production increased contraction in both trained groups. Acetylcholine induced relaxation was similar in all experimental groups showing predominant NO-dependency. Elastin and smooth muscle cell actin density was reduced in female rats after aerobic training. This study shows that, as a result of a 12-wk-long training, there are sex differences in renal arterial responses following exercise training. Swimming moderates renal artery vasoconstriction in male animals, whereas it depresses elastic fiber and smooth muscle actin density in females.NEW & NOTEWORTHY We provided the first detailed analysis of the adaptation of the renal artery after aerobic training in male and female rats. As a result of a 12-wk-long training program, the pharmacological responses of renal arteries changed only in male animals. In phenylephrine-induced contraction, cyclooxygenase-mediated vasoconstriction mechanisms lost their significance in female rats, whereas NO-dependent relaxation became a significant contraction reducing factor in both sexes. Early structural changes, such as reduced elastin and smooth muscle cell actin evolves in females.

Functional amyloids in the human body.

Amyloids have long been associated with a variety of human degenerative diseases. Discoveries indicate, however, that there are several amyloids that serve functional roles in the human body. These amyloids are involved in a variety of biological processes ranging from storage of peptide hormones to necroptosis of cells. Additionally, there are distinct differences between toxic amyloids and their functional counterparts including kinetics of assembly/disassembly and structural features. This digest article surveys the biological roles of functional amyloids found in the human body, key differences between functional and toxic amyloids, and potential therapeutic applications.

Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery.

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk.

Effects of Testosterone Deficiency and Angiotensin II-Induced Hypertension on the Biomechanics of Intramural Coronary Arteries.

BACKGROUND: Andropause and hypertension also increase the risk of coronary artery damage. AIM: To investigate the effect of testosterone deficiency and hypertension on intramural coronary vessels. METHODS: 4 groups of 8-week-old Sprague-Dawley rats were studied: control male (Co, n=10), orchidectomized male (OCT, n=13), angiotensin (AII) hypertensive male (AII, n=10), and AII hypertensive and OCT (AII + OCT, n=8). Surgical orchidectomy was performed, and an osmotic minipump was inserted for chronic angiotensin II infusion (100 ng/min/kg). After 4 weeks, spontaneous tone and biomechanical properties of the intramural coronary resistance artery were investigated in vitro, by pressure microarteriography. OUTCOMES: Morphology and biomechanics of the intramural coronaries were evaluated: the outer diameter, wall thickness-to-lumen diameter ratio, and tangential wall stress in the contracted and relaxed states. RESULTS: The outer diameter was reduced in OCT and AII + OCT groups (on 50 mmHg 315 ± 20 Co; 237 ± 21 OCT; 291 ± 16 AII, and 166 ± 12 µm AII + OCT). The increased wall thickness-to-lumen diameter ratio resulted in lower tangential wall stress in AII + OCT rats (on 50 mmHg 19 ± 2 Co; 24 ± OCT; 26 ± 5 AII, and 9 ± 1 kPa AII + OCT). Spontaneous tone was increased in the hypertensive rats (AII and AII + OCT groups) (on 50 mmHg 7.7 ± 1.8 Co; 6.1 ± 1.4 OCT; 14.5 ± 3.0 AII, and 17.4 ± 4.1 % AII + OCT). CLINICAL IMPLICATIONS: Andropause alone can be considered as a cardiovascular risk factor that will further exacerbate vascular damage in hypertension. STRENGTHS & LIMITATIONS: A limitation of our study is that it was performed on relatively young rats, and the conclusions might not apply to coronary remodelling in older animals with slower adaptation processes. CONCLUSIONS: Testosterone deficiency and hypertension damage the mechanical adaptation of the vessel wall additively: double noxa caused inward eutrophic remodeling and increased tone. Jósvai A, Török M, Mátrai M, et al. Effects of Testosterone Deficiency and Angiotensin II-Induced Hypertension on the Biomechanics of Intramural Coronary Arteries. J Sex Med 2020;17:2322-2330.

Sulfonamide derivatives as multi-target agents for complex diseases.

Sulfonamide derivatives are frequently seen structural motifs in medicinal chemistry. Almost a century after Gerhard Domagk's pioneering work leading to the first sulfonamide antibiotic Prontosil, sulfa-drugs are still widely utilized in various pharmaceutical applications due to their antibacterial, antiviral, antimalarial, antifungal, anticancer, antidepressant, or other properties. In the past few years, the interest in sulfonamides has increased as their broad range of bioactivity and versatile structure make them excellent candidates for repurposing old drugs or developing new multi-target agents in the emerging field of polypharmacology. This digest aims to provide an overview of recent advances in sulfonamide-based bioactive compounds, their importance in drug discovery and development emphasizing multi-target approaches for complex diseases, and their novel contribution to contemporary medicinal chemistry.

Synthesis and application of ß-carbolines as novel multi-functional anti-Alzheimer's disease agents.

The design, synthesis and assessment of ß-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aß self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aß complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Physiological and pathological left ventricular hypertrophy of comparable degree is associated with characteristic differences of in vivo hemodynamics.

Left ventricular (LV) hypertrophy is a physiological or pathological response of LV myocardium to increased cardiac load. We aimed at investigating and comparing hemodynamic alterations in well-established rat models of physiological hypertrophy (PhyH) and pathological hypertrophy (PaH) by using LV pressure-volume (P-V) analysis. PhyH and PaH were induced in rats by swim training and by abdominal aortic banding, respectively. Morphology of the heart was investigated by echocardiography. Characterization of cardiac function was completed by LV P-V analysis. In addition, histological and molecular biological measurements were performed. Echocardiography revealed myocardial hypertrophy of similar degree in both models, which was confirmed by post-mortem heart weight data. In aortic-banded rats we detected subendocardial fibrosis. Reactivation of fetal gene program could be observed only in the PaH model. PhyH was associated with increased stroke volume, whereas unaltered stroke volume was detected in PaH along with markedly elevated end-systolic pressure values. Sensitive indexes of LV contractility were increased in both models, in parallel with the degree of hypertrophy. Active relaxation was ameliorated in athlete's heart, whereas it showed marked impairment in PaH. Mechanical efficiency and ventriculo-arterial coupling were improved in PhyH, whereas they remained unchanged in PaH. Myocardial gene expression of mitochondrial regulators showed marked differences between PaH and PhyH. We provided the first comparative hemodynamic characterization of PhyH and PaH in relevant rodent models. Increased LV contractility could be observed in both types of LV hypertrophy; characteristic distinction was detected in diastolic function (active relaxation) and mechanoenergetics (mechanical efficiency), which might be explained by mitochondrial differences.

Strain and strain rate by speckle-tracking echocardiography correlate with pressure-volume loop-derived contractility indices in a rat model of athlete's heart.

Contractile function is considered to be precisely measurable only by invasive hemodynamics. We aimed to correlate strain values measured by speckle-tracking echocardiography (STE) with sensitive contractility parameters of pressure-volume (P-V) analysis in a rat model of exercise-induced left ventricular (LV) hypertrophy. LV hypertrophy was induced in rats by swim training and was compared with untrained controls. Echocardiography was performed using a 13-MHz linear transducer to obtain LV long- and short-axis recordings for STE analysis (GE EchoPAC). Global longitudinal (GLS) and circumferential strain (GCS) and longitudinal (LSr) and circumferential systolic strain rate (CSr) were measured. LV P-V analysis was performed using a pressure-conductance microcatheter, and load-independent contractility indices [slope of the end-systolic P-V relationship (ESPVR), preload recruitable stroke work (PRSW), and maximal dP/dt-end-diastolic volume relationship (dP/dtmax-EDV)] were calculated. Trained rats had increased LV mass index (trained vs. control; 2.76 ± 0.07 vs. 2.14 ± 0.05 g/kg, P < 0.001). P-V loop-derived contractility parameters were significantly improved in the trained group (ESPVR: 3.58 ± 0.22 vs. 2.51 ± 0.11 mmHg/µl; PRSW: 131 ± 4 vs. 104 ± 2 mmHg, P < 0.01). Strain and strain rate parameters were also supernormal in trained rats (GLS: -18.8 ± 0.3 vs. -15.8 ± 0.4%; LSr: -5.0 ± 0.2 vs. -4.1 ± 0.1 Hz; GCS: -18.9 ± 0.8 vs. -14.9 ± 0.6%; CSr: -4.9 ± 0.2 vs. -3.8 ± 0.2 Hz, P < 0.01). ESPVR correlated with GLS (r = -0.71) and LSr (r = -0.53) and robustly with GCS (r = -0.83) and CSr (r = -0.75, all P < 0.05). PRSW was strongly related to GLS (r = -0.64) and LSr (r = -0.71, both P < 0.01). STE can be a feasible and useful method for animal experiments. In our rat model, strain and strain rate parameters closely reflected the improvement in intrinsic contractile function induced by exercise training.

Sulfonamides as multifunctional agents for Alzheimer's disease.

Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aß self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aß self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.

SHBG Levels Do Not Correlate with Insulin Levels in PCOS with Appropriate Fasting Insulin Sensitivity.

Introduction: There are several phenotypes of polycystic ovarian syndrome (PCOS), and the different phenotypes may differ metabolically. Methods: In the present retrospective study, women with PCOS having normal fasting insulin sensitivity (n = 88) were compared with women with PCOS showing impaired insulin sensitivity (n = 46) using the HPCOS (Hungarian Polycystic ovarian syndrome) database. Results: The impaired insulin sensitivity group has significantly higher body mass index (BMI) and HOMA index than the normal fasting insulin sensitivity group (BMI (kg/m2): 22.0 vs. 28.1, p < 0.0001, HOMA index: 0.96 vs. 2.38, p < 0.0001). The sex hormone binding globulin (SHBG) level was significantly lower, and the free androgen index proved itself significantly higher in the impaired insulin sensitivity group (p < 0.05). Linear regression analysis showed a negative association of BMI with SHBG levels in both groups, while BMI had a positive correlation with insulin concentrations in both groups. However, the SHBG levels were negatively associated with insulin concentrations in the impaired insulin sensitivity group, but this inverse association could not be observed in the normal fasting insulin sensitivity group. Conclusions: The inverse linear correlation of SHBG with HOMA index and serum insulin level is not evident in all PCO syndrome phenotypes, thus SHBG has limited applicability for characterizing carbohydrate metabolism and serum insulin sensitivity.

Sociodemographic and Medical Characteristics of Women Applied for Emergency Contraception-A Retrospective Observational Study.

Background: Lifestyle factors significantly impact overall health. Our aim was to assess reproductive health awareness among patients who applied for emergency contraceptive pills. Methods: This present retrospective observational study between July 2021 and September 2021 is embedded in the MEEC (Motivation and Epidemiology of Emergency Contraceptive Pill) based on the study cohort of a Hungarian data bank containing follow-up data of 447 women who applied for EC telemedicine consultation. Collected data: age, history of previous pregnancy, lifestyle factors like smoking, alcohol consumption, sexual characteristics: partner consistency and protection during intercourse, cervical cancer screening within the past 2 years, previous HPV screening, and the preference for future contraceptive methods. The investigation also compiled accurate data on intercourse (elapsed time to request a medical consultation). Lifestyle factors were scored. Results: The more health-conscious patients were quicker to report for a post-event pill. Earlier pregnancies and older age were associated with greater reproductive health awareness. Conclusions: Reproductive health awareness is increased by previous pregnancies and older age. More health-conscious women consult a doctor earlier, which can reduce the chance of various health damage. Our study emphasizes the significance of lifestyle factor influence on reproductive health decisions.

Motivators for emergency contraception: Previous pregnancy and condom rupture.

Objectives: Little is known about the motivations to apply for emergency contraception (EC). Our first aim was to explore the motivating circumstances to use EC as fast as possible. Our second aim was to explore the contraceptive method of the population seeking EC. Study design: This present retrospective observational study between July 2021 and September 2021 is embedded in the MEEC (Motivation and Epidemiology of Emergency Contraceptive Pill) based on the study cohort of a Hungarian data bank containing follow-up data of 455 women applied for EC telemedicine consultation. Variables assessed were: age, gynecological history (pregnancies, abortions, miscarriages), data of the intercourse (elapsed time, contraceptive method), and data of the menstrual cycle, and relationship status. Results: Of all patients, 59.3 % reported condom rupture, 29.5 % no protection, and 11.2 % other. Patients using condom applied for EC significantly sooner than those using no protection and using other protective methods. A significantly shorter elapsed time was observed in patients with a history of a previous pregnancy. No significant relationship was seen between the way of protection, previous pregnancies, and surprisingly the time of ovulation despite the obvious intention of avoiding pregnancy. Conclusions: This is the first study to examine the potential role of epidemiologic factors as motivators for EC on the basis of a large patient cohort. Our study demonstrates the significant role of condom rupture/use and the history of previous pregnancies to be the strongest motivators for EC.

Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly.

The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid ß (Aß) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Aß species, as well. Atomic force microscopy was also applied to monitor the morphology of Aß deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid.

Design, synthesis and biological activity of multifunctional α,ß-unsaturated carbonyl scaffolds for Alzheimer's disease.

A series of compounds containing an α,ß-unsaturated carbonyl moiety, such as chalcones and coumarins were designed, synthesized and tested in a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations included the inhibition of cholinesterases (AChE, BuChE), the inhibition of amyloid beta (Aß) self-assembly and the disassembly of preformed Aß oligomers. Several compounds showed excellent potential as multifunctional compounds for AD. Docking studies for 16 that performed well in all the assays gave a clear interpretation of various interactions in the gorge of AChE. Based on the results, the long-chain coumarin scaffold appears to be a promising structural template for further AD drug development.

[Herniated amniotic sac through uterine dehiscence at the 30th gestational week after prior laparoscopic salpingectomy]. / Elozetes laparoszkópos salpingectomiát követo hegszétválás és buroksérv a várandósság 30. hetében.

Uterine rupture is a rare complication during pregnancy which may even lead to the death of the mother and the fetus. In this report, the management of a herniated amniotic sac associated with uterine dehiscence is presented. A 25-year-old primigravida at 30 weeks with a history of a previous unilateral salpingectomy was transferred to our hospital with the potential diagnosis of a herniated amniotic sac, which was discovered during a routine ultrasound scan. The patient had no prior complaints or any other signs that would have indicated a serious condition during her pregnancy. She underwent an emergency cesarean section and a two-layer closure of the lesion. An adequate suture during laparoscopic salpingectomy provides prevention of uterine rupture during subsequent pregnancies. A medical history with a previous laparoscopic dehiscence should necessitate a more frequent sonographic observation during pregnancy. Orv Hetil. 2023; 164(25): 988-992.

[Molar pregnancy in postmenopause]. / Molaterhesség postmenopausában.

Hydatidiform mole is an extremely rare gestational trophoblastic disease. The pathogenesis is unique in that the maternal tumor arises from pregnancy tissue. In terms of occurrence, it mainly affects women of reproductive age. In our case report, a 53-year-old female patient was diagnosed with molar pregnancy as the background of her perimenopausal bleeding disorder. Mola is a high-risk disease because the symptoms can be deceiving and may be very similar to those of an incomplete miscarriage, ectopic pregnancy or perimenopausal bleeding. Appropriate diagnosis is key to terminating the pregnancy as soon as possible. The purpose of our case report is to draw attention to the atypical appearance of molar pregnancy; in relation to our perimenopausal female patient, we review the basic principles of treatment of hydatidiform mole and present the diagnostic and therapeutic management of a successfully completed case. Orv Hetil. 2023; 164(7): 273-277.

[Emergency contraception.] / Esemény utáni fogamzásgátlás.

INTRODUCTION: Emergency contraception is an effective and safe solution for preventing unwanted pregnancies. Many methods of emergency contraception are used, which have different mechanisms of action and time frames. OBJECTIVE: Providing information to healthcare professionals and decision-makers based on the literature data about the target populations of emergency contraception, evidence-based modern methods, their effectiveness, and practical application for the purpose of reducing the incidence of unintended pregnancies. METHODS: We conducted a systematic literature search in MEDLINE (PubMed), Embase and Scopus databases based on relevant keywords, for publications that were published between 1960 and 2023. RESULTS: 23 clinical professional publications were selected that examined the effectiveness of oral and long-term usable contraceptives as emergency contraceptives. Our research results were interpreted in terms of weight, breastfeeding, time elapsed since the intercourse and future contraceptive plans, which help to select the most appropriate emergency contraceptive for healthcare professionals. CONCLUSION: Based on the literature data, our systematic review provides assistance for choosing between the available oral levonorgestrel, ulipristal acetate, and intrauterine contraceptive devices available in Hungary based on effectiveness, target population, and accessibility. We support the healthcare governance in creating up-to-date professional guidelines to improve the availability of emergency contraception and, consequently, enhance reproductive health. Orv Hetil. 2023; 164(44): 1736-1748.

The Importance of Nutrition in Menopause and Perimenopause-A Review.

Menopause is associated with an increased prevalence of obesity, metabolic syndrome, cardiovascular diseases, and osteoporosis. These diseases and unfavorable laboratory values, which are characteristic of this period in women, can be significantly improved by eliminating and reducing dietary risk factors. Changing dietary habits during perimenopause is most effectively achieved through nutrition counseling and intervention. To reduce the risk factors of all these diseases, and in the case of an already existing disease, dietary therapy led by a dietitian should be an integral part of the treatment. The following review summarizes the recommendations for a balanced diet and fluid intake, the dietary prevention of cardiovascular diseases, the role of sleep, and the key preventive nutrients in menopause, such as vitamin D, calcium, vitamin C, B vitamins, and protein intake. In summary, during the period of perimenopause and menopause, many lifestyle factors can reduce the risk of developing all the diseases (cardiovascular disease, insulin resistance, type 2 diabetes mellitus, osteoporosis, and tumors) and symptoms characteristic of this period.