Receptor Sensitivity Research Articles

Cinacalcet Improves Erythropoietin Resistance in Patients with Secondary Hyperparathyroidism Receiving Dialysis Treatment

Introduction: Chronic Kidney Disease (CKD) is recognized as a major global public health problem. Dialysis is the mainstay of treatment for patients with end-stage renal disease and can prolong survival in patients with CKD. As patient survival increases, the treatment of complications becomes more important. CKD-mineral and bone disorders (CKD-MBD) and renal anemia are common complications in patients with CKD. Cinacalcet is a calcimimetic for the treatment of Secondary Hyperparathyroidism (SHPT) in adult dialysis patients, which regulates the synthesis and secretion of parathyroid hormone by increasing the sensitivity of calcium-sensitive receptors. This retrospective study evaluated the efficacy of cinacalcet in dialysis patients. Method: Forty-seven patients on dialysis with elevated parathyroid hormone were included. The selected patients have regular follow-up visits in our outpatient clinic and regular use of cinacalcet for no less than 6 months. Result: During the 6-month efficacy evaluation phase, cinacalcet not only reduced the levels of the intact parathyroid hormone (iPTH, P ≤ 0.05), serum calcium (P ≤ 0.01), and Ca×P (P ≤ 0.05) but also reduced weekly erythropoietin dosage (P ≤ 0.01) and erythropoietin resistance index (ERI, P ≤ 0.05). Conclusion: While controlling SHPT in patients with CKD, cinacalcet reduced EPO resistance and improved renal anemia. In conclusion, cinacalcet not only decreased the levels of the iPTH, serum calcium, and Ca×P but also reduced weekly EPO dosage and ERI levels. Controlling SHPT in patients with CKD, cinacalcet also reduced ERI and improved renal anemia.

Effects of attentional focus on spatial localization of distal body parts and touch in two-arm position matching.

This study investigated how the judgment of proximal joint position can be affected by touch alone, focused attention on the distal body part, or touch spatial localization. Participants completed a two-arm elbow joint position-matching task, in which they indicated the location of one forearm by the placement of the other. In four test conditions, matching was performed during (1) detection of touch (tactile stimulation of index finger pads), (2) spatial localization of fingers (attention focused on the position of index finger pads), (3) spatial localization of touch on fingers (attention focused on tactile stimulation of index finger pads), and (4) detection of touch but localization of fingers (tactile stimulation of index finger pads, but attention focusing on the spatial position of the pads). In the first experiment (n = 23), the sensitivity of muscle spindle receptors in both reference and indicator arms was reduced and equalized by both-slack conditioning. In the second experiment (n = 20), the illusion of excessive elbow flexion in the reference arm and excessive extension in the indicator arm was generated through extension-flexion conditioning. In the first experiment, the accuracy and precision of matching were unaffected in any test condition. In the second experiment, participants made amplified undershooting errors under attention-focused conditions. In conclusion, focused attention on the location of a distal body part and touch affects both the spatial localization of the limb and tactile remapping only when the perceived forearm position is misinterpreted due to imbalanced proprioceptive input from antagonistic arm muscles.

Role of ryanodine receptor cooperativity in Ca2+-wave-mediated triggered activity in cardiomyocytes.

Ca2+ waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca2+ waves using physiologically realistic models has remained a major challenge. Existing models with low Ca2+ sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca2+ transient amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of delayed after-depolarizations resort to unrealistic cell architectures to produce Ca2+ waves with a normal Ca2+ transient amplitude. Here, we address these challenges by incorporating RyR cooperativity into a physiologically detailed model with a realistic cell architecture. We represent RyR cooperativity phenomenologically through a Hill coefficient within the sigmoid function of RyR open probability. Simulations in permeabilized myocytes with high Ca2+ sensitivity reveal that a sufficiently large Hill coefficient is required for Ca2+ wave propagation via the fire-diffuse-fire mechanism. In intact myocytes, propagating Ca2+ waves can occur only within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca2+-wave-mediated triggered activity, including phase 2 and phase 3 early after-depolarizations and high-frequency voltage-Ca2+ oscillations. These oscillations feature an elevated take-off potential with depolarization mediated by the L-type Ca2+ current. The model also sheds light on the roles of luminal gating of RyRs and the mobile buffer ATP in the genesis of these arrhythmogenic phenomena. KEY POINTS: Existing mathematical models of Ca2+ waves use an excessively large Ca2+-release current or unrealistic diffusive coupling between release units. Our physiologically realistic model, using a Hill coefficient in the ryanodine receptor (RyR) gating function to represent RyR cooperativity, addresses these limitations and generates organized Ca2+ waves at Hill coefficients ranging from ∼5 to 10, as opposed to the traditional value of 2. This range of Hill coefficients gives a spark rate neither too low, thereby enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during the plateau phase of the action potential. Additionally, the model generates Ca2+-wave-mediated phase 2 and phase 3 early after-depolarizations, and coupled membrane voltage with Ca2+ oscillations mediated by the L-type Ca2+ current. This study suggests that pharmacologically targeting RyR cooperativity could be a promising strategy for treating cardiac arrhythmias linked to Ca2+-wave-mediated triggered activity.

Sympathetic transduction to blood pressure in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) are more than twice as likely to die from a cardiovascular event than those with normal kidney function. Although CKD may increase resting sympathetic activity, quantification of resting sympathetic outflow alone does not account for the ensuing vasoconstriction, and blood pressure (BP) change (i.e., sympathetic transduction). Patients with CKD have been reported to exhibit elevated α-adrenergic receptor sensitivity, which may predispose this population to greater sympathetic transduction. We tested the hypothesis that patients with CKD have augmented sympathetic transduction to BP. In 16 patients with CKD, 17 bodyweight-matched (BWM) controls, and 11 lean controls of a similar age muscle sympathetic nerve activity (MSNA) and beat-to-beat BP were continuously recorded during quiet supine rest. Signal averaging was used to quantify changes in mean arterial pressure (MAP) and total vascular conductance (TVC) following spontaneous bursts of MSNA. Peak increases in MAP following MSNA bursts were not different among patients with CKD and the control groups (CKD: 2.3 ± 1.1mmHg; BWM controls: 2.1 ± 1.0mmHg; lean controls: 1.7 ± 0.9mmHg; P = 0.28). Likewise, nadir reductions in TVC following all bursts of MSNA were not different among patients with CKD and either control group (P = 0.69). Both patients with CKD and controls had graded increases in MAP and decreases in TVC with increasing burst size, which were not different among groups (all P > 0.05). In summary, these data indicate that patients with CKD do not have augmented sympathetic transduction to BP.

Investigation of Radioxenon Probability Density Functions at IMS Radionuclide Stations Using a Monte Carlo Method for Background Estimation

Abstract The International Monitoring System, the primary means of verification of the Comprehensive Nuclear-Test-Ban Treaty, monitors the planet for any sign of a nuclear explosion. Regarding the International Monitoring System radionuclide stations, it is known that radioxenon released from nuclear facilities such as medical isotope production facilities and nuclear power plants influences the stations. For the purposes of monitoring nuclear explosions, it is important to better understand the radioxenon background based on these nuclear facilities. The probability density functions of background activity concentration at IMS radionuclide stations are estimated using a Monte Carlo method based on emissions from known nuclear facilities and source receptor sensitivity data. This paper describes two case studies of radioxenon detections at radionuclide stations applying the developed approach. This method could be one of several prospective approaches to predict the activity concentrations of isotopes of radioxenon at radionuclide stations in Comprehensive Nuclear Test-Ban Treaty Organization’s (CTBTO’s) prototype xenon background estimation tool software. It can also be used in characterization of CTBT-relevant nuclear events for expert technical analysis. Plain Language Summary Civil nuclear power stations and medical isotope production facilities release radioisotopes of xenon during their normal operations. These emissions would make it harder to detect xenon produced from any nuclear weapon test that might occur. A method is described that starts with information about civil releases and produces a statistical description of the concentrations of isotopes measured at stations designed to detect nuclear tests. This information makes it possible to enhance nuclear explosion detection performance.

Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms.

Background: Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. Methods: We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Results: Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), andTCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Conclusions: Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.

Using a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate Ca2+ Cycling, Voltage Dependence, and Spark Characteristics.

Previous studies have observed alterations in excitation-contraction (EC) coupling during end-stage heart failure that include action potential and calcium (Ca2+) transient prolongation and a reduction of the Ca2+ transient amplitude. Underlying these phenomena are the downregulation of potassium (K+) currents, downregulation of the sarcoplasmic reticulum Ca2+ ATPase (SERCA), increase Ca2+ sensitivity of the ryanodine receptor, and the upregulation of the sodium-calcium (Na=-Ca2+) exchanger. However, in human heart failure (HF), debate continues about the relative contributions of the changes in calcium handling vs. the changes in the membrane currents. To understand the consequences of the above changes, they are incorporated into a computational human ventricular myocyte HF model that can explore the contributions of the spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The reduction of transient outward K+ current (Ito) is the main membrane current contributor to the decrease in RyR2 open probability and L-type calcium channel (LCC) density which emphasizes its importance to phase 1 of the action potential (AP) shape and duration (APD). During current-clamp conditions, RyR2 hyperphosphorylation exhibits the least amount of Ca2+ release from the SR into the cytosol and SR Ca2+ fractional release during a dynamic slow-rapid-slow (0.5-2.5-0.5 Hz) pacing, but it displays the most abundant and more lasting Ca2+ sparks two-fold longer than a normal cell. On the other hand, under voltage-clamp conditions, HF by decreased SERCA and upregulated INCX show the least SR Ca2+ uptake and EC coupling gain, as compared to HF by hyperphosphorylated RyR2s. Overall, this study demonstrates that the (a) combined effect of SERCA and NCX, and the (b) RyR2 dysfunction, along with the downregulation of the cardiomyocyte's potassium currents, could substantially contribute to Ca2+ mishandling at the spark level that leads to heart failure.

Abnormal EEG Effects of Acute Apomorphine Injection in 5xFAD Transgenic Mice Are Partially Normalized in Those Chronically Pretreated with Apomorphine: The Time-Frequency Clustering of EEG Spectra.

In experimental and clinical studies of pharmacological treatments for Alzheimer's disease (AD), the electroencephalogram (EEG) frequency spectrum approach has demonstrated its efficacy in determining the characteristics of pathological changes in the functioning of different cerebral structures, interconnections between them, and disturbances in the brain neurotransmitter systems. The main results have been obtained in frames of traditionally used so-called "classical" EEG frequency bands: delta, theta, alpha, and beta. This unified approach simplifies comparing data from different studies but loses the dynamic peculiarities of the effects because of their time-dependent transition through the borders of the "classical" bands. In this study on non-narcotized freely moving 5xFAD transgenic mice, a model of AD, chronically pretreated with a non-selective dopamine (DA) receptor agonist, apomorphine (APO), we analyze the transitory EEG effects of acute APO injection in different brain areas by use of our "time-frequency" clustering program. The acute injection of APO was used to compare DA receptor sensitivity in 5xFAD mice pretreated with either APO or saline vs. wild-type (WT) mice pretreated with saline. After acute APO injection, the clusters of enhanced EEG activity centered in the theta-alpha frequency range observed in WT mice disappeared in 5xFAD mice pretreated with saline and practically recovered in 5xFAD mice pretreated with APO. In 5xFAD mice pretreated with saline, the sensitivity of DA receptors was disturbed; chronic APO pretreatment mainly recovered this characteristic in 5xFAD mice. The "clustering" of pharmacological EEG effects and their time-dependent transition between classical frequency bands is a new effective approach for analyzing cerebral neurotransmission in neurodegenerative pathologies.

Pain tolerance and the thresholds of human sensory and motor axons to single and repetitive bursts of kilohertz-frequency stimulation.

Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier-frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10kHz carrier-frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20Hz for 1s. Participants tolerated higher current amplitudes with both carrier-frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce sensory and motor-threshold responses and to obtain a maximal motor response (Mmax). When the current at pain tolerance was normalised to the current at Mmax, participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier-frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons. KEY POINTS: Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier-frequency waveform is thought to be less painful than conventional pulsed currents. For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier-frequency stimulation than conventional stimulation. However, compared to conventional stimulation, carrier-frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (Mmax). When current at pain tolerance was normalised to current at Mmax, participants tolerated lower stimulus intensities with carrier-frequency waveforms than conventional stimulation. Carrier-frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons.

Chronic ethanol exposure in mice evokes pre- and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons.

GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol-naïve mice to investigate its impact on anxiety-related behaviour. The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR-dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired-pulse depression of GABAA receptor-dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol-treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety-related behaviour in ethanol-naïve mice. Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre- and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety-related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder.

Оценка влияния многокомпонентного комплекса с растительными экстрактами на основные параметры эректильной функции у мужчин.

Introduction. Male infertility is a complex disease with many potential causes, including hormonal imbalance, anatomical problems, genetic factors, lifestyle factors, and more. Currently, there is a fairly large group of infertile men with unspecified causes of the disease. Introduction. Erection is a neurovascular process that is regulated by psychological factors and endocrine status. Erectile dysfunction can be based on various causes – psychological, neurological, endocrinological, vascular – arterial and related to impaired functioning of the cavernous bodies, or a combination of the above factors. The assessment of the factors that lead to erectile dysfunction in this particular man is fundamentally important for choosing the right treatment tactics. Among the many methods of correcting erectile disorders, herbal components and other biologically active substances are currently actively used to enhance testosterone synthesis, libido stimulation and erection. Objective. To evaluate the effect of the dietary supplement Vuka Forte on the main parameters of erectile function in men. Materials and methods. This article describes analyzed data from 45 men with erectile disorders of various etiologies, with complaints of a decrease in the quality of adequate erections of mild and moderate severity at the age of 34 to 55 years and the duration of the disease from 6 months to 9 years, who were recommended dietary supplement Vuka Forte. The complex was used by men 1 tablet 1 time per day with meals in the morning for 1 month. The results were evaluated 1 month after the start of taking the Vuka Forte dietary supplement. An objective (physical) examination was performed. Laboratory diagnostics included the determination of the following indicators: biochemical profile, total testosterone, albumin, LH (luteinizing hormone), insulin, glucose, glycosylated hemoglobin, lipid profile. The assessment of the quality of life and sexual function of men was carried out on the IPSS scale (International System for the Summary Assessment of Prostate Diseases, Lower Urinary Tract Symptoms (GMP)) and IIEF-15 (International index of erectile function). Results. According to the results of our work, the use of Vuka Forte dietary supplements in men with various erectile disorders, including those associated with metabolic disorders, especially in the early stages of its development, contributes to the restoration of insulin receptor sensitivity, normalization of carbohydrate and lipid metabolism, endothelial function. The use of Vuka Forte dietary supplements is accompanied by a statistically significant improvement in erectile function to the level of mild erectile disorders or their absence, stabilization of the hormonal background, and improvement in the quality of life in general. Conclusions. The results indicate the possibility of using the dietary supplement Vuka Forte as a multicomponent complex for men with various erectile dysfunctions, including those associated with metabolic disorders of any severity, and its use is justified.

Analysis of Factors Affecting Self-care of Type 2 Diabetes Mellitus Patients

Diabetes mellitus is a chronic disease characterized by increased blood sugar levels due to interference with insulin production or decreased sensitivity of insulin receptors in the body. Diabetes itself cannot be cured so it requires intensive treatment, especially proper self-care to support the patient's life. The aim of this study was to determine the factors that influence the self-caring of type 2 diabetes mellitus patients undergoing outpatient care at Dr. RSUD. Moewardi Surakarta. This research was carried out observationally with a cross-sectional design. Self-care measurement uses the Diabetes Self-care Management Questionnaire (DSMQ) instrument. The results of this study show that of the 167 responses involved, 131 respondents (78.4%) had good self-care and 36 respondents (21.6%) had poor self-care. Data analysis using chi-square showed that age, gender, education, marital status, employment and duration of DM had no effect on the patient's self-care (p>0.05).

Autoregulated splicing of TRA2β programs T cell fate in response to antigen-receptor stimulation.

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human. TRA2β-PE splicing, seen during cancer and infection, was required for TCR-induced effector T cell expansion and function. Tra2β-PE skipping enhanced T cell response to antigen by increasing TCR sensitivity. As antigen levels decreased, Tra2β-PE reinclusion allowed T cell survival. Finally, we found that TRA2β-PE was first included in the genome of jawed vertebrates that were capable of TCR gene rearrangements. We propose that TRA2β-PE splicing acts as a gatekeeper of TCR sensitivity to shape T cell fate.

Insulin injection rotation and Diabetes Mellitus nutritional management education

The management of Diabetes Mellitus (DM) involves implementing a healthy lifestyle and pharmacological interventions through the administration of anti-hyperglycemia drugs. An essential aspect of treating DM patients is insulin administration, which facilitates glucose transportation into cells. This study evaluated the effectiveness of insulin injection rotation and nutritional management education for DM.The literature search utilized the keywords "education,"AND "insulin injection," AND "nutritional management," AND "DM", ranged 2021-2023 Searches were conducted on various databases, including Proquest, NCBI, BMC, ScienceDirect, and other relevant platforms such as Google Scholar.Ten journal articles pertinent to the subject matter were identified in the study. Findings indicate that nutritional education facilitates overall health improvement in individuals with DM, contributing to maintaining average body weight and near-normal blood glucose levels. It also enhances lipid profile and insulin receptor sensitivity while being a preventive measure against acute or chronic complications such as hyperglycemia. It is noted that selecting the appropriate injection site can significantly impact patients' blood glucose levels. While it is recommended to administer injections at consistent locations, repetitive use of the same site may pose risks of side effects, such as lipodystrophy.After conducting a comprehensive review of ten journal articles, it has been concluded that insulin injection rotation and nutritional management education are effective for managing DM.

Tiaogan Bushen Xiaoji Formula Enhances the Sensitivity of Estrogen Receptor- Positive Breast Cancer to Tamoxifen by Inhibiting the TGF-β/SMAD Pathway.

The resistance to endocrine therapy can lead to recurrence and metastasis of breast cancer (BC), affecting the survival period. Tiaogan Bushen Xiaoji (TGBSXJ) Formula, a traditional Chinese medicine (TCM) decoction, has been widely used in the treatment of estrogen receptor-positive (ER+) BC. However, the underlying mechanism of TGBSXJ Formula in ER+BC treatment has not been totally elucidated. Network pharmacology (NP) and RNA sequencing were used to predict the candidate ingredients and explore the potential targets of TGBSXJ Formula. Then, the results of NP and RNA sequencing were investigated by in vitro experiments. Active ingredients of TGBSXJ Formula mainly included Mangiferin, Rutin, Anemarrhena asphodeloides saponin BII, Ganoderic acid A and Acacetin, etc. A protein-protein interaction (PPI) network was created based on the active ingredients of TGBSXJ Formula and target genes of ER+ BC, in which TGF-β, MMP2 and SMAD3 were defined as the hub genes. In vitro experiments showed that TGBSXJ Formula significantly inhibited the viability, colony ability and migration of ER+ BC cells, and significantly increased the sensitivity to TAM. Western blot analysis showed that TGBSXJ Formula significantly downregulated TGF-β, E-cadherin, MMP2, MMP9, N-cadherin, p-Smad2 and p-Smad3 in ER+ BC cells. TGBSXJ Formula increases the sensitivity of ER+ BC cells to TAM by inhibiting the TGF-β/Smad signaling pathway.

Sex differences in sympathetic transduction in black and white adults: implications for racial disparities in hypertension and cardiovascular disease risk.

The prevalence of hypertension in non-Hispanic black (BL) individuals is the greatest of any racial/ethnic group. Whereas women generally display lower rates of hypertension than men of the same background, BL women display a similar if not greater burden of hypertension compared with BL men. The risk for cardiovascular disease and related events is also highest in BL individuals. Given the importance of the sympathetic nervous system for the regulation of the cardiovascular system, a growing body of literature has investigated sympathetic function in BL and non-Hispanic white (WH) individuals. Here, we are focused on emerging evidence indicating that sympathetic function may be altered in BL individuals, with particular emphasis on the process by which bursts of muscle sympathetic nerve activity (MSNA) are transduced into vasoconstriction and increases in blood pressure (sympathetic vascular transduction). To synthesize this growing body of literature we discuss sex and race differences in 1) sympathetic outflow, 2) sympathetic vascular transduction, and 3) adrenergic receptor sensitivity. Sex differences are discussed foremost, to set the stage for new data indicating a sex dimorphism in sympathetic regulation in BL individuals. Specifically, we highlight evidence for a potential neurogenic phenotype including greater adiposity-independent sympathetic outflow and enhanced sympathetic vascular transduction in BL men that is not observed in BL women. The implications of these findings for the greater hypertension and cardiovascular disease risk in BL adults are discussed along with areas that require further investigation.

Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway.

Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

Treatment of erectile dysfunction by intracavernosal administration of mesenchymal stem cells in patients with diabetes mellitus.

The purpose of study is to assess and analyse the effectiveness of their use in the treatment of erectile dysfunction in patients with diabetes mellitus. The literature search was conducted using systematic methods and analysis in databases such as Web of Science, Scopus, PubMed, Elsevier, and Springer, with 41 sources included for further review. The study highlights microangiopathic and neuropathic links as key factors in erectile dysfunction development in diabetic patients, stemming from endothelial dysfunction and conductivity disturbances. Mesenchymal stem cell therapy from bone marrow, adipose tissue, and umbilical cord mitigates pathogenic impact through regenerative and anti-apoptotic effects. Due to this, most studies indicate high efficacy of the treatment and rapid therapeutic action through intracavernosal administration. Some studies suggest an increase in the body's receptor sensitivity to other drugs, such as sildenafil. From the perspective of further research on this issue, standardising the preparation of stem cells and the treatment method using a large sample size is essential to introduce such a method as an extremely promising therapy for this delicate issue in men into practical medicine. The practical value of the study lies in the systematisation of information on different sources of mesenchymal stem cells for treating erectile dysfunction.

Behavioral tests of the insulin-cholinergic-dopamine link in nucleus accumbens and inhibition by high fat-high sugar diet in male and female rats

It was previously shown in striatal slices obtained from male rats that insulin excites cholinergic interneurons and increases dopamine (DA) release via α4β2 nicotinic receptors on DA terminals. The effect of insulin on DA release was blocked either by maintaining rats on a high sugar-high fat (HS-HF) diet that induced hyperinsulinemia and nucleus accumbens (NAc) insulin receptor insensitivity, or applying the α4β2 antagonist DHβE. In vivo, NAc shell insulin inactivation decreased a glucose lick microstructure parameter indicative of hedonic impact in male and female rats, and prevented flavor-nutrient learning, tested only in males. The HS-HF diet decreased hedonic impact in males but not females, and prevented flavor-nutrient learning, tested only in males. The present study extends testing to more fully assess the translation of brain slice results to the behaving rat. Insulin inactivation by antibody microinjection in NAc shell was found to decrease the number of lick bursts emitted and average lick burst size, measures of incentive motivation and hedonic impact respectively, for a wide range of glucose concentrations in male and female rats. In contrast, the HS-HF diet decreased these lick parameters in males but not females. Follow-up two-bottle choice tests for 10 % versus 40 % glucose showed decreased intake of both concentrations by males but increased intake of 40 % glucose by females. In a further set of experiments, it was predicted that α4β2 receptor blockade would induce the same behavioral effects as insulin inactivation. In females, DHβE microinjection in NAc shell decreased both lick parameters for glucose as predicted, but in males only the number of lick bursts emitted was decreased. DHβE also decreased the number of lick bursts emitted for saccharin by females but not males. Finally, DHβE microinjection in NAc shell decreased flavor-nutrient learning in both sexes. The few discrepancies seen with regard to the hypothesized insulin-nicotinic-dopaminergic regulation of behavioral responses to nutritive sweetener, and its inhibition by HS-HF diet, are discussed with reference to sex differences in DA dynamics, female resistance to diet-induced metabolic morbidities, and extra-striatal cholinergic inputs to NAc.

Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature.

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients.