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Artificial intelligence-assisted repurposing of lubiprostone alleviates tubulointerstitial fibrosis.Translational Research : the Journal of... Dec 2023Tubulointerstitial fibrosis (TIF) is the most prominent cause which leads to chronic kidney disease (CKD) and end-stage renal failure. Despite extensive research, there...
Tubulointerstitial fibrosis (TIF) is the most prominent cause which leads to chronic kidney disease (CKD) and end-stage renal failure. Despite extensive research, there have been many clinical trial failures, and there is currently no effective treatment to cure renal fibrosis. This demonstrates the necessity of more effective therapies and better preclinical models to screen potential drugs for TIF. In this study, we investigated the antifibrotic effect of the machine learning-based repurposed drug, lubiprostone, validated through an advanced proximal tubule on a chip system and in vivo UUO mice model. Lubiprostone significantly downregulated TIF biomarkers including connective tissue growth factor (CTGF), extracellular matrix deposition (Fibronectin and collagen), transforming growth factor (TGF-β) downstream signaling markers especially, Smad-2/3, matrix metalloproteinase (MMP2/9), plasminogen activator inhibitor-1 (PAI-1), EMT and JAK/STAT-3 pathway expression in the proximal tubule on a chip model and UUO model compared to the conventional 2D culture. These findings suggest that the proximal tubule on a chip model is a more physiologically relevant model for studying and identifying potential biomarkers for fibrosis compared to conventional in vitro 2D culture and alternative of an animal model. In conclusion, the high throughput Proximal tubule-on-chip system shows improved in vivo-like function and indicates the potential utility for renal fibrosis drug screening. Additionally, repurposed Lubiprostone shows an effective potency to treat TIF via inhibiting 3 major profibrotic signaling pathways such as TGFβ/Smad, JAK/STAT, and epithelial-mesenchymal transition (EMT), and restores kidney function.
Topics: Mice; Animals; Lubiprostone; Artificial Intelligence; Drug Repositioning; Transforming Growth Factor beta1; Kidney Diseases; Transforming Growth Factor beta; Fibrosis; Biomarkers; Epithelial-Mesenchymal Transition; Kidney
PubMed: 37541485
DOI: 10.1016/j.trsl.2023.07.010 -
Biomolecules Jul 2023Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets...
Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets accelerate fibrin formation and thrombin generation, two final reactions of the coagulation cascade. We investigated the effects of antiplatelet drugs on platelet impact in these reactions and platelet ability to expose PS. Washed human platelets were incubated with acetylsalicylic acid (ASA), ticagrelor, ASA in combination with ticagrelor, ruciromab (glycoprotein IIb-IIIa antagonist), or prostaglandin E1 (PGE1). Platelets were not activated or activated by collagen and sedimented in multiwell plates, and plasma was added after supernatant removal. Fibrin formation (clotting) was monitored in a recalcification assay by light absorbance and thrombin generation in a fluorogenic test. PS exposure was assessed by annexin V staining using flow cytometry. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, prolonged the lag phase and decreased the maximum rate of plasma clotting and decreased the peak and maximum rate of thrombin generation. Inhibition was observed when platelets were not treated with exogenous agonists (activation by endogenous thrombin) and pretreated with collagen. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, decreased PS exposure on washed platelets activated by thrombin and by thrombin + collagen. PS exposure on activated platelets in whole blood was lower in patients with acute coronary syndrome receiving ticagrelor + ASA in comparison with donors free of medications. These results indicate that antiplatelet drugs are able to suppress platelet coagulation activity not only in vitro but also after administration to patients.
Topics: Humans; Platelet Aggregation Inhibitors; Blood Platelets; Ticagrelor; Thrombin; Alprostadil; Blood Coagulation; Aspirin; Fibrin; Collagen
PubMed: 37509160
DOI: 10.3390/biom13071124 -
Cells Jun 2023Stem cell transplantation has recently demonstrated a significant therapeutic efficacy in various diseases. Multilineage-differentiating stress-enduring (Muse) cells are... (Review)
Review
Stem cell transplantation has recently demonstrated a significant therapeutic efficacy in various diseases. Multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant endogenous pluripotent stem cells that were first reported in 2010. Muse cells can be found in the peripheral blood, bone marrow and connective tissue of nearly all body organs. Under basal conditions, they constantly move from the bone marrow to peripheral blood to supply various body organs. However, this rate greatly changes even within the same individual based on physical status and the presence of injury or illness. Muse cells can differentiate into all three-germ-layers, producing tissue-compatible cells with few errors, minimal immune rejection and without forming teratomas. They can also endure hostile environments, supporting their survival in damaged/injured tissues. Additionally, Muse cells express receptors for sphingosine-1-phosphate (S1P), which is a protein produced by damaged/injured tissues. Through the S1P-S1PR2 axis, circulating Muse cells can preferentially migrate to damaged sites following transplantation. In addition, Muse cells possess a unique immune privilege system, facilitating their use without the need for long-term immunosuppressant treatment or human leucocyte antigen matching. Moreover, they exhibit anti-inflammatory, anti-apoptotic and tissue-protective effects. These characteristics circumvent all challenges experienced with mesenchymal stem cells and induced pluripotent stem cells and encourage the wide application of Muse cells in clinical practice. Indeed, Muse cells have the potential to break through the limitations of current cell-based therapies, and many clinical trials have been conducted, applying intravenously administered Muse cells in stroke, myocardial infarction, neurological disorders and acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection. Herein, we aim to highlight the unique biological properties of Muse cells and to elucidate the advantageous difference between Muse cells and other types of stem cells. Finally, we shed light on their current therapeutic applications and the major obstacles to their clinical implementation from laboratory to clinic.
Topics: Humans; Cell Differentiation; Alprostadil; COVID-19; SARS-CoV-2; Pluripotent Stem Cells; Stem Cell Transplantation
PubMed: 37443710
DOI: 10.3390/cells12131676 -
Portuguese Journal of Cardiac Thoracic... Jul 2023Buerger's disease is a distal segmental nonatherosclerotic vasculopathy that involves the inferior and superior limbs of smoker males younger than 45 years old. This...
Buerger's disease is a distal segmental nonatherosclerotic vasculopathy that involves the inferior and superior limbs of smoker males younger than 45 years old. This article aims to describe a clinical case and revise the literature about Buerger's disease. A 45-year-old smoker male repeatedly visited the emergency department for refractory pain and inflammatory signs in the right hallux. After developing ulcers in the right foot, Doppler ultrasonography revealed segmental occlusion of distal arteries of that limb. It was also observed in arteriography "corkscrew" collaterals. Autoimmune, thrombophilic and cardiovascular diseases were excluded. Analgesia, antibiotics and alprostadil were implemented. As a result, the patient stopped smoking and was submitted to minor amputation with complete healing, after which he remained asymptomatic. Buerger's disease is a diagnosis of exclusion. Therefore, smoking cessation is the most effective treatment and is crucial to prevent disease progression.
Topics: Humans; Male; Middle Aged; Thromboangiitis Obliterans; Arteries; Alprostadil; Pain; Smoking
PubMed: 37418773
DOI: 10.48729/pjctvs.259 -
Urologiia (Moscow, Russia : 1999) Jul 2023Blood flow parameters in cavernous arteries during full-erection phase on Doppler ultrasonography are associated with intracavernosal pressure and, consequently, with...
INTRODUCTION
Blood flow parameters in cavernous arteries during full-erection phase on Doppler ultrasonography are associated with intracavernosal pressure and, consequently, with penile rigidity.
AIM
To examine the relationship between blood flow parameters in cavernous arteries and the penile rigidity.
MATERIALS AND METHODS
A total of 54 healthy men and patients with erectile dysfunction of various degrees of severity, with mean age of 43,0 +/- 2,2 years ranging from 18 to 74 years, were included in the study. Erectile function was examined and 81 Doppler ultrasonography were performed after intracavernosal injection of alprostadil (10 mcg). In full-erection phase, peak systolic velocity (PSV) and systolic acceleration (SA) were measured, as well as resistive index (RI). Mean values were calculated for both cavernous arteries. Penile rigidity was assessed in three ways: clinical evaluation according to I. Goldstein, measurement of surface rigidity and evaluation of longitudinal rigidity.
RESULTS
During Doppler ultrasonography a strong correlation of penile rigidity with RI (0,71-0,85) and SA (0,63-0,69) was found. Indirect assessment of penile rigidity using PSV values was less precise. With RI values close to 1,0, SA is a more reliable method for indirect rigidity assessment.
CONCLUSION
Penile blood flow parameters, RI and SA, allow to evaluate a degree of rigidity and to eliminate subjectivity of the specialist performing the examination, as well as to obtain a range of penile rigidity values.
Topics: Male; Humans; Infant, Newborn; Penis; Penile Erection; Erectile Dysfunction; Hemodynamics; Ultrasonography, Doppler, Color
PubMed: 37417415
DOI: No ID Found -
Cardiology in the Young Feb 2024The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The...
The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The intravenous infusion is well established in loading infusion and maintenance with an onset of action of 30 minutes until 2 hours or even more. Our aim is to report three patients with pulmonary atresia that presented hypercyanotic spell due to a ductal spasm during cardiac catheterisation in whom the administration of a bolus of alprostadil reversed the spasm and increased pulmonary flow, immediately stabilising the condition of the patients allowing subsequent successful stent placement with no serious complications or sequelae after the administration of the bolus. More studies are needed to make a recommendation regarding the use of alprostadil in bolus in cases where the ductal spasm might jeopardise the life of the patient.
Topics: Infant, Newborn; Humans; Alprostadil; Ductus Arteriosus; Ductus Arteriosus, Patent; Heart Defects, Congenital; Spasm
PubMed: 37403735
DOI: 10.1017/S1047951123001403 -
BMJ Open Jun 2023Individuals who access at-risk mental state (ARMS) services often have unusual sensory experiences and levels of distress that lead them to seek help. The Managing...
Use of a targeted, computer/web-based guided self-help psychoeducation toolkit for distressing hallucinations (MUSE) in people with an at-risk mental state for psychosis: protocol for a randomised controlled feasibility trial.
INTRODUCTION
Individuals who access at-risk mental state (ARMS) services often have unusual sensory experiences and levels of distress that lead them to seek help. The Managing Unusual Sensory Experiences (MUSE) treatment is a brief symptom targeted intervention that draws on psychological explanations to help account for unusual experiences. Practitioners use formulation and behavioural experiments to support individuals to make sense of their experiences and enhance coping strategies. The primary objective of this feasibility trial is to resolve key uncertainties before a definitive trial and inform parameters of a future fully powered trial.
METHODS AND ANALYSIS
88 participants aged 14-35 accepted into ARMS services, experiencing hallucinations/unusual sensory experiences which are considered by the patient to be a key target problem will be recruited from UK National Health Service (NHS) sites and randomised using 1:1 allocation (stratified by site, gender, and age) to either 6-8 sessions of MUSE or time-matched treatment as usual. Participants and therapists will be unblinded, research assessors are blinded. Blinded assessment will occur at baseline, 12 weeks and 20 weeks postrandomisation. Data will be reported in line with Consolidated Standards of Reporting Trials. Primary trial outcomes are feasibility outcomes, primary participant outcomes are functioning and hallucinations. Additional analysis will investigate potential psychological mechanisms and secondary mental well-being outcomes. Trial progression criteria follows signal of efficacy and uses an analytical framework with a traffic-light system to determine viability of a future trial. Subsequent analysis of the NHS England Mental Health Services Data Set 3 years postrandomisation will assess long-term transition to psychosis.
ETHICS AND DISSEMINATION
This trial has received Research Ethics Committee approval (Newcastle North Tyneside 1 REC; 23/NE/0032). Participants provide written informed consent; young people provide assent with parental consent. Dissemination will be to ARMS Services, participants, public and patient forums, peer-reviewed publications and conferences.
TRIAL REGISTRATION NUMBER
ISRCTN58558617.
Topics: Humans; Adolescent; Alprostadil; State Medicine; Feasibility Studies; Treatment Outcome; Psychotic Disorders; Hallucinations; Computers; Internet; Randomized Controlled Trials as Topic
PubMed: 37399435
DOI: 10.1136/bmjopen-2023-076101 -
Pediatric Emergency Care Nov 2023Pediatric patients who are critically unwell require rapid access to central vasculature for administration of life-saving medications and fluids. The intraosseous (IO)...
OBJECTIVES
Pediatric patients who are critically unwell require rapid access to central vasculature for administration of life-saving medications and fluids. The intraosseous (IO) route is a well-described method of accessing the central circulation. There is a paucity of data surrounding the use of IO in neonatal and pediatric retrieval. The aim of this study was to review the frequency, complications, and efficacy of IO insertion in neonatal and pediatric patients in retrieval.
METHODS
A retrospective review of cases referred to neonatal and pediatric emergency transfer service, New South Wales over the epoch 2006 to 2020. Medical records documenting IO use were audited for patient demographic data, diagnosis, treatment details, IO insertion and complication statistics, and mortality data.
RESULTS
Intraosseous access was used in 467 patients (102 neonatal/365 pediatric). The most common indications were sepsis, respiratory distress, cardiac arrest, and encephalopathy. The main treatments were fluid bolus, antibiotics, maintenance fluids, and resuscitation drugs. Return of spontaneous circulation after resuscitation drugs occurred in 52.9%; perfusion improved with fluid bolus in 73.1%; blood pressure improved with inotropes in 63.2%; seizures terminated with anticonvulsants in 88.7%. Prostaglandin E1 was given to eight patients without effect. Intraosseous access-related injury occurred in 14.2% of pediatric and 10.8% of neonatal patients. Neonatal and pediatric mortality rates were 18.6% and 19.2%, respectively.
CONCLUSIONS
Survival in retrieved neonatal and pediatric patients who required IO is higher than previously described in pediatric and adult cohorts. Early insertion of an IO facilitates early volume expansion, delivery of critical drugs, and allows time for retrieval teams to gain more definitive venous access. In this study, prostaglandin E1 delivered via a distal limb IO had no success in reopening the ductus arteriosus.
Topics: Adult; Infant, Newborn; Child; Humans; New South Wales; Alprostadil; Emergency Medical Services; Infusions, Intraosseous; Heart Arrest
PubMed: 37391199
DOI: 10.1097/PEC.0000000000003005 -
Toxins Jun 2023Intracavernosal injections of botulinum toxin A (BTX/A ) may be effective for difficult-to-treat erectile dysfunction (ED). This is a retrospective case series study of...
Safety and Effectiveness of Repeated Botulinum Toxin A Intracavernosal Injections in Men with Erectile Dysfunction Unresponsive to Approved Pharmacological Treatments: Real-World Observational Data.
Intracavernosal injections of botulinum toxin A (BTX/A ) may be effective for difficult-to-treat erectile dysfunction (ED). This is a retrospective case series study of the effectiveness of repeated off-label BTX/A (onabotulinumtoxinA 100U, incobotulinumtoxinA 100U or abobotulinumtoxinA 500U) in men with ED and insufficient response to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandinE1 intracavernosal injections (PGE1 ICIs), defined as an International Index of Erectile Function-Erectile Function domain score (IIEF-EF) < 26 on treatment. Further injections were performed on patients' requests, and the files of men who underwent at least two injections were reviewed. The response to BTX/A was defined as the achievement of the minimally clinically important difference in IIEF-EF adjusted to the severity of ED on treatment at baseline. Out of 216 men treated with BTX/A and PDE5-Is or PGE1-ICIs, 92 (42.6%) requested at least a second injection. The median time since the preceding injection was 8.7 months. In total, 85, 44 and 23 men received, respectively, two, three and four BTX/A . The overall response rate was 77.5%: 85.7% in men with mild ED, 79% for moderate ED and 64.3% for severe ED on treatment. The response increased with repeated injections: 67.5%, 87.5% and 94.7%, respectively, after the second, third and fourth injections. Post-injection changes in IIEF-EF were similar across injections. The time from injection to request for a further injection varied little. Four men reported penile pain at the time of injection (1.5% of all injections), and one experienced a burn at the penile crus. Repeated BTX/A injections combined with PDE5-Is or PGE1-ICIs produced an effective and durable response, with acceptable safety.
Topics: Male; Humans; Erectile Dysfunction; Penile Erection; Alprostadil; Retrospective Studies; Botulinum Toxins, Type A; Phosphodiesterase 5 Inhibitors; Treatment Outcome
PubMed: 37368683
DOI: 10.3390/toxins15060382