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Human endothelial cells bioactivate organic nitrates to nitric oxide: implications for the reinforcement of endothelial defence mechanisms.

Although in therapeutic use for more than a century, the mode of cellular action of organic nitrates remains incompletely understood. Despite ample experimental evidence from animal studies to show that nitrates are metabolized to NO in the vascular smooth muscle, direct demonstration of such an activity in human vascular cells is still lacking. Moreover, the role of the endothelium in modulating the pharmacodynamic action of nitrates is far from clear. We therefore aimed to investigate whether or not human endothelial cells are capable of bioactivating these drugs to NO and whether the amount

[Effect of automated blood volume control on the incidence of intra-dialysis hypotension].

INTRODUCTION: Hypotension is the major cause of morbidity during hemodialysis (HD), occurring in about 20% of HD patients. Hypovolemia generated from blood volume (BV) contraction dependent on the ultrafiltration rate (UFR) and on the plasma refilling rate, is a major factor in the pathogenesis of intradialytic hypotension (IDH). Hemocontrol biofeedback system (Hemocontrol, Hospal, HBS), incorporated in the bicarbonate HD, modulates BV contraction rate by adjusting the UFR and dialysate conductivity (DC) in order to obtain predetermined BV trajectories. In the present study, HBS treatment was

Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: involvement of ETA and ETB receptors.

1. Although recent observations suggest that endothelin-1 (ET-1) may play a role in the pathogenesis of asthma, to date little is known about the effects of ET-1 on parameters other than bronchoconstriction. The objectives of the present experiments were to study whether intravenously administered ET-1 could exert pro-inflammatory actions in the guinea-pig lung and to assess the involvement of endothelin ETA and ETB receptors in these events by using the ETA receptor-selective antagonist, FR 139317, the novel ETA/ETB receptor antagonist, bosentan and the ETB receptor-selective agonist, IRL 162

The normal and pathological physiology of brain water.

The physicochemical properties of water enable it to act as a solvent for electrolytes, and to influence the molecular configuration and hence the function--enzymatic in particular--of polypeptide chains in biological systems. The association of water with electrolytes determines the osmotic regulation of cell volume and allows the establishment of the transmembrane ion concentration gradients that underlie nerve excitation and impulse conduction. Fluid in the central nervous system is distributed in the intracellular and extracellular spaces (ICS, ECS) of the brain parenchyma, the cerebrospin

[Arterial hypertension in patients on chronic hemodialysis].

Arterial hypertension is frequent among chronically dialyzed patients. The kidney obviously plays a major role in arterial blood pressure co … arteriovenous anastomosis, disequilibrium syndrome, changes in osmotic gradient of both extra- and intracellular spaces with resultant arteriolar wall oedema, erythrocyte amount, hypoxia, composition of dialysis fluid (sodium concentration), plasma osmotic pressure, metabolic acidosis and other factors. More recently, natriuretic hormone has also been indentified as …

Electrolytes and water in the brain and cerebrospinal fluid of the foetal sheep and guinea-pig.

1. Samples of cisternal cerebrospinal fluid (c.s.f.) and blood plasma have been obtained nearly simultaneously from foetal sheep of different ages, the foetus having been exteriorized and maintained in a normal state with respect to its blood gases and arterial pH. The brains were removed from these foetuses and also from foetal guinea-pigs after exsanguination.2. A comprehensive study has been made of the concentrations of water, chloride, sodium, potassium, calcium and magnesium in blood plasma, c.s.f. and brain from foetal sheep and in brain from foetal guinea-pigs during development in ute

Chronic effects of AJ-9677 on energy expenditure and energy source utilization in rats.

The effects of AJ-9677 on metabolic parameters were examined in rats that had or had not been chronically treated with this beta3-adrenoceptor agonist. A challenge administration of AJ-9677 increased both the temperature of brown adipose tissue and energy expenditure in both groups of rats. However, whereas the former effect was subject to desensitization, the latter effect was augmented by prior chronic administration of AJ-9677. Whereas a challenge administration of AJ-9677 induced a decrease in the respiratory quotient that persisted for at least 15 h in rats pretreated with vehicle, the in

SpatialDINO: A Self-Supervised 3D Vision Transformer that enables Segmentation and Tracking in Crowded Cellular Environments.

UNLABELLED: Quantitative, time-resolved 3D fluorescence microscopy can reveal complex cellular dynamics in living cells and tissues. Broader use remains limited by the difficulty of identifying, segmenting, and tracking objects of different size and shape in crowded intracellular environments in low-contrast, anisotropic, monochromatic image volumes. Objects overlap, deform, appear and disappear, and span wide ranges of size and intensity. Classical segmentation pipelines typically require high signal-to-noise data and rely on intensity heuristics with hand-tuned postprocessing that generalize

Brain capillaries in Alzheimer's disease.

Alzheimer's disease is the most common cause of irreversible dementia, affecting mostly the presenile and senile age, shaping a tragic profile in the epilogue of the life of the suffering people. Due to the severity and the social impact of the disease an ongoing research activity is in climax nowadays, associated with many legal, social, ethical, humanitarian, philosophical and economic considerations. From the neuropathological point of view the disease is characterized by dendritic pathology, loss of synapses and dendritic spines, affecting mostly selective neuronal networks of critical imp

Extracellular cAMP activates molecular signalling pathways associated with sperm capacitation in bovines.

STUDY QUESTION: Is extracellular cAMP involved in the regulation of signalling pathways in bovine sperm capacitation? SUMMARY ANSWER: Extracellular cAMP induces sperm capacitation through the activation of different signalling pathways that involve phospholipase C (PLC), PKC/ERK1-2 signalling and an increase in sperm Ca2+ levels, as well as soluble AC and cAMP/protein kinase A (PKA) signalling. WHAT IS KNOWN ALREADY: In order to fertilize the oocyte, ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, known as capacitation. This correlates with a number

STUDIES IN ULTRAFILTRATION.

We are submitting this series of experiments as observed facts, realizing that there are so many uncertainties in this form of indirect observation that great caution must be exercised in drawing conclusions of any kind. The most serious of the possible errors involved is that the active substances which we have studied, the enzyme-the bacteriophage-and the several varieties of virus, may not be free in our suspensions, but are adsorbed to larger particles. The peculiar difficulties encountered in filtering herpes virus particularly suggest a source of error of this kind, and if we are right i

The Acidic Microenvironment: Is It a Phenotype of All Cancers? A Focus on Multiple Myeloma and Some Analogies with Diabetes Mellitus.

Multiple myeloma (MM) is a hematological malignancy with a poor prognosis while with a long and progressive outcome. To date, the therapeutic options are restricted to few drugs, including thalidomide or its derivates and autologous transplantation including stem-cell transplantation. More recently, the use of both proteasome inhibitors and monoclonal antibodies have been included in MM therapy, but the clinical results are still under evaluation. Unfortunately, death rates (within the 5-year overall survival rates) are still very high (45%), with no relevant improvement over the past 10 years

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… In MM and DM cells with dysfunctional mitochondria under normoxemia or hypoxemia conditions, large amounts of H + are produced and released into the intracellular spaces ( Figure 1 B). … Further, the NHE contributes to the release of protons from the intracellular fluid to the extracellular one: HCO 3 − -coupled transporters also contributes to reduction of proton concentration (with pH increase) in the intracellular space via incorporation of HCO 3 − into intracellular space; via the …

Одинокий квантовый Sodium MRI на 3T для разделения сигналов Sodium и Mono и B-T2.

Из-за десятикратной разницы в концентрации натрия на мембранах, которая активно поддерживается насосом с натрием-потассием (Na+-K+), клеточный ионный баланс очень чувствительн. Разрывы в этом насосе или мембранной целостности, наблюдаемые в таких неврологических расстройствах, как эпилепсия, множественный склероз, биполярное заболевание и легкая травма головного мозга, приводят к увеличению внутриклеточного натрия. Однако это изменение клеточного уровня часто маскируется доминирующим внеклеточным сигналом натрия, что затрудняет проведение различия между популяциями натрия с моно- и биэкспонент

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… To that goal, we assigned all mono-T 2 sodium to extracellular space and all bi-T 2 sodium to intracellular space, although they may co-exist in both extra- and intracellular spaces. … The estimates (mean and SD) were made in the regions of interest (ROIs) of gray matter (GM) and white matter (WM) across three continuous slices via equations (6 - 8) using sodium concentrations C e x = 145 mM for extracellular space and C i n = 15 mM for intracellular space. …

Никотинамид Аденин динуклеотид дополняет Cuprizone испытуемые многочисленные поведенческие изменения в C57BL/6J Mice.

ЦЕЛЬ: Изучение вопроса о том, может ли добавка никотинамида аденина динуклеотида (NAD+) улучшить поведенческие изменения в модели мыши, опьяненной мышью. МЕТОДЫ: Six- Неделю назад мыши C57BL/6J были разделены на three группы: two еда 0.2% cuprizone chow (cuprizone и cuprizone + NAD+ группы), а другая группа получила нормальную грызуновую (контрольную группу) 4 недель. Мыши в чашезоне + NAD+ группа получили 250 мг/кг/сут NAD+ interperitononyly один раз в день, в то время как другие мыши получали засос одновременно. Были проведены поведенческие тесты на пространственное воспоминание (Моррисский

Calcium Signalling in Breast Cancer Associated Bone Pain.

Calcium (Ca2+) is involved as a signalling mediator in a broad variety of physiological processes. Some of the fastest responses in human body like neuronal action potential firing, to the slowest gene transcriptional regulation processes are controlled by pathways involving calcium signalling. Under pathological conditions these mechanisms are also involved in tumoral cells reprogramming, resulting in the altered expression of genes associated with cell proliferation, metastatisation and homing to the secondary metastatic site. On the other hand, calcium exerts a central function in nocicepti

Progressive Elevation of Store-Operated Calcium Entry-Associated Regulatory Factor (SARAF) and Calcium Pathway Dysregulation in Multiple Sclerosis.

Multiple Sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination and neuronal damage in the central nervous system. Dysregulation of calcium homeostasis, particularly through the Store-Operated Calcium Entry-Associated Regulatory Factor (SARAF), has been implicated in MS pathogenesis. This study investigated SARAF, STIM1, and Orai1 expression patterns and their relationship to calcium homeostasis in 45 Bahraini MS patients and 45 matched healthy controls using ELISA and real-time PCR analyses. MS patients showed significantly elevated serum SARAF levels in both early (19

Earlier onset of chemotherapy-induced neuropathic pain in females by ICAM-1-mediated accumulation of perivascular macrophages.

Sex differences in the pathogenesis of a variety of diseases have drawn increasing attention. However, it remains unclear whether such differences exist in chemotherapy-induced neuropathic pain. Here, we conducted a retrospective analysis of clinical case data and found that peripheral sensory disorders occurred earlier in females than in males following bortezomib (BTZ) treatment in patients with multiple myeloma. BTZ treatment led to an early elevation of intercellular adhesion molecule-1, which triggered the infiltration of peripheral monocytes into the perivascular region of the spinal cor

Cyclic Peptides in Modern Drug Discovery: Trends and Therapeutic Directions.

Peptide therapeutics are an important drug modality due to their high specificity, favorable safety, and expanding design potential. Among them, cyclic peptides occupy a space between small molecules and biologics, offering improved rigidity, stability, and target engagement. This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades. Results show a steady rise in academic publications and patents, reflecting growing interest across discovery and development. Notably, oral administration is gaining attention, indicating progress

Целенаправленная деградация белка разрушает ненаркомные цели, чтобы обратить вспять иммунное уклонение и терапию устойчивости к раку.

Таргетированная деградация белков (ТД) использует эндогенные протеолитические системы — систему убиквина и протеасомы и лизосомальные пути — для селективного удаления белков, вызывающих болезни, которые не реагируют на традиционное ингибирование. В онкологической иммунотерапии ТД разрушает критические иммунодепрессивные узлы в экзоцитоплазматическом, мембранном и цитоплазматическом компартментах, перепрограммируя микросреду опухоли от иммунологически «холодной» к «горячей» состоянию. Эта статья рассматривает молекулярные принципы инженерии бифункциональных деградаторов и обобщает клинические д

The γ-secretase complex: from discovery to a therapeutic target.

γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor