Notoginsenoside R1 attenuates ischemic heart failure by modulating MDM2/ß arrestin2-mediated ß2-adrenergic receptor ubiquitination.

ß2 adrenergic receptor (ß2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged ß2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased ß2AR levels and decreased ß2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and ß-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between ß-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of ß2AR to improve CHF.

Using the sympathetic system, beta blockers and alpha-2 agonists, to address acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) manifests as an acute inflammatory lung injury characterized by persistent hypoxemia, featuring a swift onset, high mortality, and predominantly supportive care as the current therapeutic approach, while effective treatments remain an area of active investigation. Adrenergic receptors (AR) play a pivotal role as stress hormone receptors, extensively participating in various inflammatory processes by initiating downstream signaling pathways. Advancements in molecular biology and pharmacology continually unveil the physiological significance of distinct AR subtypes. Interventions targeting these subtypes have the potential to induce specific alterations in cellular and organismal functions, presenting a promising avenue as a therapeutic target for managing ARDS. This article elucidates the pathogenesis of ARDS and the basic structure and function of AR. It also explores the relationship between AR and ARDS from the perspective of different AR subtypes, aiming to provide new insights for the improvement of ARDS.

Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3ß activity in mouse partial hepatectomy.

INTRODUCTION: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear. OBJECTIVES: This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx. METHODS: In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3ß and Flag-tagged GSK3ß, α2-ADR antagonist, GSK3ß inhibitor, AKT inhibitor were used to identify the role of GSK3ß in DEX-mediated autophagic flux and hepatocyte proliferation. RESULTS: Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3ß activity by SB216763 and si-GSK3ß enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor. CONCLUSION: Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3ß activity in an α2-ADR-dependent manner.

Adrenergic Urticaria: An Updated Review.

It can be difficult to delineate the cause of urticarial eruptions, and in chronic cases, it can be a challenging condition to effectively treat. Several forms of urticarial eruptions are well documented and established. Our review focuses on a form of urticaria that is less commonly reported: adrenergic urticaria. In this review, we aim to consolidate the literature in the hopes that this urticarial subtype is considered in urticarial differentials, as well as highlight potential gaps in the research and future directions in treatment options.

Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview.

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

Berberine prevents against myocardial injury induced by acute ß-adrenergic overactivation in rats.

The overactivation of ß-adrenergic receptors (ß-ARs) can result in acute myocardial ischemic injury, culminating in myocardial necrosis. Berberine (BBR) has exhibited promising potential for prevention and treatment in various heart diseases. However, its specific role in mitigating myocardial injury induced by acute ß-AR overactivation remains unexplored. This study aimed to investigate the effects and underlying mechanisms of BBR pretreatment in a rat model of acute ß-AR overactivation induced by a single dose of the nonselective ß-adrenergic agonist isoprenaline (ISO). Rats were pretreated with saline or BBR (100 mg/kg/day) via gavage for 14 consecutive days, followed by a subcutaneous injection of ISO or saline on the 14th day. The findings indicated that BBR pretreatment significantly attenuated myocardial injury in ISO-stimulated rats, as evidenced by reduced pathological inflammatory infiltration, necrosis, and serum markers of myocardial damage. Additionally, BBR decreased oxidative stress and inflammation in the system and heart. Furthermore, BBR pretreatment enhanced myocardial ATP levels, improved mitochondrial dysfunction through increased Drp1 phosphorylation, and augmented myocardial autophagy. In a CoCl2-induced H9c2 cell hypoxic injury model, BBR pretreatment mitigated cellular injury, apoptosis, and oxidative stress while upregulating Drp1 and autophagy-associated proteins. Mechanistically, BBR pretreatment activated AKT, AMPK, and LKB1 both in vivo and in vitro, implicating the involvement of the AKT and LKB1/AMPK signaling pathways in its cardioprotective effects. Our study demonstrated the protective effects of BBR against myocardial injury induced by acute ß-AR overactivation in rats, highlighting the potential of BBR as a preventive agent for myocardial injury associated with ß-adrenergic overactivation.

An Unusual Case of Paroxysmal Third-Degree Atrioventricular Block: Thinking Outside the Box.

During the assessment of a third-degree atrioventricular (AV) block in a patient with syncope, different etiologies should be considered and evaluated. Extrinsic vagal paroxysmal AV block, extrinsic idiopathic AV block and intrinsic paroxysmal AV block are among the types of third-degree AV block in the differential diagnoses. Extrinsic vagal paroxysmal third-degree atrioventricular block (EV-AVB) is linked to parasympathetic influence on cardiac conduction and can be observed in bladder distention and urinary retention. Topical and ophthalmic beta-blockers have shown systemic effects such as bradycardia with and without syncope. We present the case of an 80-year-old male with symptomatic EV-AVB likely precipitated by bladder outlet obstruction and chronic use of an ophthalmic beta-blocker, often overlooked causes of third-degree AV block.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Stroke Risk Reduction in Migraine Patients Using Propranolol: Evidence from Two Large-Scale Real-World Data Analyses.

Background: Propranolol, a non-selective beta-blocker, is commonly used for migraine prevention, but its impact on stroke risk among migraine patients remains controversial. Using two large electronic health records-based datasets, we examined stroke risk differences between migraine patients with- and without- documented use of propranolol. Methods: This retrospective case-control study utilized EHR data from the Vanderbilt University Medical Center (VUMC) and the All of Us Research Program. Migraine patients were first identified based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria using diagnosis codes. Among these patients, cases were defined as those with a primary diagnosis of stroke following the first diagnosis of migraine, while controls had no stroke after their first migraine diagnosis. Logistic regression models, adjusted for potential factors associated with stroke risk, assessed the association between propranolol use and stroke risk, stratified by sex and migraine subtype. A Cox proportional hazards regression model was used to estimate the hazard ratio (HR) for stroke risk at 1, 2, 5, and 10 years from baseline. Results: In the VUMC database, 378 cases and 15,209 controls were identified, while the All of Us database included 267 cases and 6,579 controls. Propranolol significantly reduced stroke risk in female migraine patients (VUMC: OR=0.52, p=0.006; All of Us: OR=0.39, p=0.007), but not in males. The effect was more pronounced for ischemic stroke and in females with migraines without aura (MO) (VUMC: OR=0.60, p=0.014; All of Us: OR=0.28, p=0.006). The Cox model showed lower stroke rates in propranolol-treated female migraine patients at 1, 2, 5, and 10 years (VUMC: HR=0.06-0.55, p=0.0018-0.085; All of Us: HR=0.23, p=0.045 at 10 years). Conclusions: Propranolol is associated with a significant reduction in stroke risk, particularly ischemic stroke, among female migraine without aura patients. These findings suggest that propranolol may benefit stroke prevention in high-risk populations.

Population pharmacokinetics of tamsulosine in patients with benign prostatic hyperplasia.

PURPOSE: The study aimed to determine the typical clearance and volume of distribution values of tamsulosin in patients with benign prostatic hyperplasia (BPH), and to identify factors with a measurable impact on the drug's elimination. METHODS: This open-label, single-arm population pharmacokinetic study involved 65 adult men with BPH who had been on tamsulosin therapy for at least seven days. The steady-state serum concentrations of tamsulosin were measured using liquid chromatography-tandem quadrupole mass spectrometry. Population pharmacokinetic parameters, their variability, and influencing factors were estimated based on a two-compartment pharmacokinetic model using NONMEM software. RESULTS: The estimated tamsulosin clearance in BPH patients was 0.719 L/h, and the steady-state volume of distribution was 32 L. Neither renal nor liver function parameters had a statistically significant effect on tamsulosin clearance. However, a positive correlation was observed between hemoglobin levels and tamsulosin clearance in the BPH patient cohort. CONCLUSION: Our investigation reveals significant associations between tamsulosin pharmacokinetics and specific characteristics of patients with lower urinary tract symptoms (LUTS) due to BPH. The study highlights that tamsulosin clearance is associated with hemoglobin levels in patients with LUTS/BPH. This study underscores the importance of considering patient-specific factors when managing BPH treatment with tamsulosin, emphasizing associations rather than causative relationships.

Exposure to Glycolysis-Enhancing Drugs and Risk of Parkinson's Disease: A Meta-Analysis.

Background: Impaired glucose and energy metabolism has been suggested as a pathogenic mechanism underlying Parkinson's disease (PD). In recent cohorts, phosphoglycerate kinase 1 activators (PGK1a) have been associated with a lower incidence of PD when compared with other antiprostatic agents that do not activate PGK1. Objective: We aimed to perform a systematic review and meta-analysis comparing the incidence of PD in patients taking PGK1a versus tamsulosin. Methods: We searched PubMed, Embase, and Cochrane Library for studies comparing PGK1a vs. tamsulosin in adults and elderly. The primary outcome was the incidence of PD. We computed hazard ratios (HR) for binary endpoints, with 95% confidence intervals (CIs). Statistical analysis was performed using Review Manager 5.4 and R (version 4.3.1). Results: A total of 678,433 participants from four cohort studies were included, of whom 287,080 (42.3%) received PGK1a. Mean age ranged from 62 to 74.7 years and nearly all patients were male. Patients taking PGK1a had a lower incidence of PD (PGK1a 1.04% vs. tamsulosin 1.31%; HR 0.80; 95% CI 0.71-0.90; p < 0.01). This result remained consistent in a sensitivity analysis excluding patients of age 60 years old or younger (PGK1a 1.21% vs. tamsulosin 1.42%; HR 0.82; 95% CI 0.71-0.95; p < 0.01). Conclusions: Glycolysis-enhancing drugs are associated with a lower incidence of PD when compared with tamsulosin in adults and elderly individuals with prostatic disease in use of alpha-blockers. Our findings support the notion of glycolysis as a potential neuroprotective mechanism in PD. Future investigations with randomized controlled trials are needed.

It has been suggested that impairment in glucose and energy metabolism is one of the mechanisms underlying the development of Parkinson's disease. In recent studies, medications traditionally prescribed for prostate diseases, called phosphoglycerate kinase 1 activators (PGK1a), have been associated with a lower incidence of Parkinson's disease when compared to other medications for the same purpose that do not activate the same energetic pathway. Therefore, we thoroughly reviewed the literature and combined the results of studies that compared both medications (PGK1a versus another medication  that  does not activate this energetic pathway, called tamsulosin), evaluating the incidence of Parkinson's disease in both groups. We included a total of 678,433 individuals, of whom 42.3% received PGK1a and 57.7% received tamsulosin. In our analysis, patients taking PGK1a had a lower incidence of Parkinson's disease when compared to the other group, even when we excluded patients younger than 60 years of age. As a result, our findings support the notion that the increase of energy metabolism is a potential neuroprotective mechanism in Parkinson's disease and future investigations are needed.

Effect of perioperative tamsulosin on successful ureteral access sheath placement and stent-related symptom relief: A double-blinded, randomized, placebo-controlled study.

PURPOSE: This study investigated the effect of administering tamsulosin before surgery on the successful insertion of a 12/14 French (F) ureteral access sheath (UAS) during the procedure, as well as the impact of preoperative and postoperative tamsulosin use on symptoms related to the ureteral stent. MATERIALS AND METHODS: This study was a randomized, single-center, double-blinded, placebo-controlled trial involving 200 patients who underwent unilateral retrograde intrarenal surgery. Patients received either tamsulosin (0.4 mg) or placebo 1 week before surgery until stent removal. Patients were randomly assigned to one of four groups. Group 1 received tamsulosin throughout the study period. Group 2 received tamsulosin before surgery and placebo after surgery. Group 3 received placebo before surgery and tamsulosin after surgery. Group 4 received placebo before and after surgery. The USSQ (Ureteral Stent Symptom Questionnaire) was completed between postoperative days 7 and 14 immediately before stent removal. RESULTS: A total of 160 patients were included in this analysis. Their mean age was 55.0±11.0 years, and 48 patients (30.0%) were female. In the group that received preoperative tamsulosin, the success rate of 12/14F UAS deployment was significantly higher than that of the preoperative placebo group (88.0 vs. 75.3%, p=0.038). Preoperative and postoperative tamsulosin did not significantly alleviate symptoms related to the ureteral stent. CONCLUSIONS: Our results revealed that preoperative administration of tamsulosin improved the success of larger-sized UAS, whereas preoperative and postoperative tamsulosin use did not significantly alleviate symptoms related to ureteral stents.

Chronic Epinephrine-Induced Endoplasmic Reticulum and Oxidative Stress Impairs Pancreatic ß-Cells Function and Fate.

Epinephrine influences the function of pancreatic ß-cells, primarily through the α2A-adrenergic receptor (α2A-AR) on their plasma membrane. Previous studies indicate that epinephrine transiently suppresses insulin secretion, whereas prolonged exposure induces its compensatory secretion. Nonetheless, the impact of epinephrine-induced α2A-AR signaling on the survival and function of pancreatic ß-cells, particularly the impact of reprogramming after their removal from sustained epinephrine stimulation, remains elusive. In the present study, we applied MIN6, a murine insulinoma cell line, with 3 days of high concentration epinephrine incubation and 2 days of standard incubation, explored cell function and activity, and analyzed relevant regulatory pathways. The results showed that chronic epinephrine incubation led to the desensitization of α2A-AR and enhanced insulin secretion. An increased number of docked insulin granules and impaired Syntaxin-2 was found after chronic epinephrine exposure. Growth curve and cell cycle analyses showed the inhibition of cell proliferation. Transcriptome analysis showed the occurrence of endoplasmic reticulum stress (ER stress) and oxidative stress, such as the presence of BiP, CHOP, IRE1, ATF4, and XBP, affecting cellular endoplasmic reticulum function and survival, along with UCP2, OPA1, PINK, and PRKN, associated with mitochondrial dysfunction. Consequently, we conclude that chronic exposure to epinephrine induces α2A-AR desensitization and leads to ER and oxidative stress, impairing protein processing and mitochondrial function, leading to modified pancreatic ß-cell secretory function and cell fate.

The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening.

Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300-2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300-2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 µM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300-2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300-2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300-2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300-2342. The docking results showed that P300-2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300-2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects.

Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or ß-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the ß-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through ß-adrenergic receptor activation.

Effects of perioperative dexmedetomidine on delayed graft function following renal transplant: a systematic review and meta-analysis.

BACKGROUND: Dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist with sedative and analgesic effects, has been suggested in recent studies to possess renoprotective properties. Dexmedetomidine may reduce the incidence of delayed graft function and contribute to effective pain control post-renal transplantation. The primary objective of this systematic review was to assess whether dexmedetomidine decreases the occurrence of delayed graft function in renal transplant patients. METHODS: Databases including MEDLINE, EMBASE, and CENTRAL were comprehensively searched from their inception until March 2023. The inclusion criteria covered all Randomized Clinical Trials (RCTs) and observational studies comparing dexmedetomidine to control in adult patients undergoing renal transplant surgery. Exclusions comprised case series and case reports. RESULTS: Ten RCTs involving a total of 1358 patients met the eligibility criteria for data synthesis. Compared to the control group, the dexmedetomidine group demonstrated a significantly lower incidence of delayed graft function (OR = 0.71, 95% CI 0.52-0.97, p = 0.03, GRADE: Very low, I2 = 0%). Dexmedetomidine also significantly prolonged time to initiation of rescue analgesia (MD = 6.73, 95% CI 2.32-11.14, p = 0.003, GRADE: Very low, I2 = 93%) and reduced overall morphine consumption after renal transplant (MD = -5.43, 95% CI -7.95 to -2.91, p < 0.0001, GRADE: Very low, I2 = 0%). The dexmedetomidine group exhibited a significant decrease in heart rate (MD = -8.15, 95% CI -11.45 to -4.86, p < 0.00001, GRADE: Very low, I2 = 84%) and mean arterial pressure compared to the control group (MD = -6.66, 95% CI -11.27 to -2.04, p = 0.005, GRADE: Very low, I2 = 87%). CONCLUSIONS: This meta-analysis suggests that dexmedetomidine may potentially reduce the incidence of delayed graft function and offers a superior analgesia profile as compared to control in adults undergoing renal transplants. However, the high degree of heterogeneity and inadequate sample size underscore the need for future adequately powered trials to confirm these findings.

Cocoa extract induces browning of white adipocytes and improves glucose intolerance in mice fed a high-fat diet.

Cocoa extract (CE) offers several health benefits, such as anti-obesity and improved glucose intolerance. However, the mechanisms remain unclear. Adipose tissue includes white adipose tissue (WAT) and brown adipose tissue. Brown adipose tissue leads to body fat reduction by metabolizing lipids to heat via uncoupling protein 1 (UCP1). The conversion of white adipocytes into brown-like adipocytes (beige adipocytes) is called browning, and it contributes to the anti-obesity effect and improved glucose tolerance. This study aimed to evaluate the effect of CE on glucose tolerance in terms of browning. We found that dietary supplementation with CE improved glucose intolerance in mice fed a high-fat diet, and it increased the expression levels of Ucp1 and browning-associated gene in inguinal WAT. Furthermore, in primary adipocytes of mice, CE induced Ucp1 expression through ß3-adrenergic receptor stimulation. These results suggest that dietary CE improves glucose intolerance by inducing browning in WAT.

Inotropic Agents: Are We Still in the Middle of Nowhere?

Inotropes are prescribed to enhance myocardial contractility while vasopressors serve to improve vascular tone. Although these medications remain a life-saving therapy in cardiovascular clinical scenarios with hemodynamic impairment, the paucity of evidence on these drugs makes the choice of the most appropriate vasoactive agent challenging. As such, deep knowledge of their pharmacological and hemodynamic effects becomes crucial to optimizing hemodynamic profile while reducing the potential adverse effects. Given this perspective, it is imperative for cardiologists to possess a comprehensive understanding of the underlying mechanisms governing these agents and to discern optimal strategies for their application across diverse clinical contexts. Thus, we briefly review these agents' pharmacological and hemodynamic properties and their reasonable clinical applications in cardiovascular settings. Critical interpretation of available data and the opportunities for future investigations are also highlighted.

Importance of IgE-Induced Unique Plasma Leakage in the Skin for Urticaria-Like Symptoms in an Anaphylaxis-Dependent Spotted Distribution of Immune Complex in Skin (ASDIS) Mouse Model.

INTRODUCTION: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model. METHODS: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue - a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined. RESULTS: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom. CONCLUSION: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.