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Journal of Liposome Research Jun 2018Light chain (AL) amyloidosis is a disease associated with significant morbidity and mortality arising from multi-organ injury induced by amyloidogenic light chain...
Light chain (AL) amyloidosis is a disease associated with significant morbidity and mortality arising from multi-organ injury induced by amyloidogenic light chain proteins (LC). There is no available treatment to reverse the toxicity of LC. We previously showed that chaperone glycoprotein clusterin (CLU) and nanoliposomes (NL), separately, restore human microvascular endothelial function impaired by LC. In this work, we aim to prepare PEGylated-nanoliposomal clusterin (NL-CLU) formulations that could allow combined benefit against LC while potentially enabling efficient delivery to microvascular tissue, and test efficacy on human arteriole endothelial function. NL-CLU was prepared by a conjugation reaction between the carboxylated surface of NL and the primary amines of the CLU protein. NL were made of phosphatidylcholine (PC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG 2000 carboxylic acid) at 70:25:5 mol%. The protective effect of NL-CLU was tested by measuring the dilation response to acetylcholine and papaverine in human adipose arterioles exposed to LC. LC treatment significantly reduced the dilation response to acetylcholine and papaverine; co-treatment of LC with PEGylated-nanoliposomal CLU or free CLU restored the dilator response. NL-CLU is a feasible and promising approach to reverse LC-induced endothelial damage.
Topics: Acetylcholine; Amyloidogenic Proteins; Amyloidosis; Arterioles; Cholesterol; Clusterin; Endothelial Cells; Endothelium, Vascular; Humans; Liposomes; Nanoparticles; Papaverine; Particle Size; Phosphatidylcholines; Polyethylene Glycols; Vasodilation
PubMed: 28103719
DOI: 10.1080/08982104.2016.1274756 -
Jornal Brasileiro de Nefrologia 2019Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate.
METHOD
This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection.
RESULTS
Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101).
CONCLUSION
Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.
Topics: Adolescent; Adult; Aged; Arteriovenous Shunt, Surgical; Female; Follow-Up Studies; Hematoma; Humans; Kidney Failure, Chronic; Male; Middle Aged; Papaverine; Prospective Studies; Renal Dialysis; Thrombosis; Treatment Outcome; Vasodilator Agents; Venous Pressure; Young Adult
PubMed: 31498862
DOI: 10.1590/2175-8239-JBN-2018-0170 -
Journal of Molecular Neuroscience : MN May 2019Studies have shown that papaverine can inhibit lipopolysaccharide (LPS)-induced microglial activation. The retinal primary microglia of newborn SD rats were isolated and...
Studies have shown that papaverine can inhibit lipopolysaccharide (LPS)-induced microglial activation. The retinal primary microglia of newborn SD rats were isolated and purified, and a LPS-induced microglia activation model was established. The protein phosphorylation level of the signaling pathway was detected by western blotting. The transcription and expression of TNF-α, IL-1β, and IL-10 were respectively detected by RT-PCR and ELISA to observe the abnormal activation of primary microglia. The cAMP inhibitor Rp-isomer, PKA inhibitor H89, and MEK inhibitor U0126 were separately added to further investigate the role of MEK/Erk in PAP inhibition of primary microglial activation and the relationship between cAMP/PKA and MEK/Erk. It was found that the level of MEK phosphorylation was upregulated after LPS stimulation, which was blocked by 10 μg/ml of papaverine.10μM U0126 significantly inhibited TNF-α and IL-1β and increased IL-10 transcription and expression in retinal microglia (P < 0.01). Both Rp-isomer and H89 upregulated the phosphorylation levels of MEK and Erk. Papaverine may inhibit inflammatory factors and promote the expression of anti-inflammatory factors through the cAMP/PKA and MEK/Erk pathway, thereby inhibiting LPS-induced activation of primary retinal microglia, and the MEK/Erk pathway may be partially regulated by cAMP/PKA, which can provide theoretical basis and experimental basis for its protection of the central nervous system.
Topics: Animals; Cells, Cultured; Cytokines; Lipopolysaccharides; MAP Kinase Signaling System; Microglia; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Papaverine; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Retina
PubMed: 30852743
DOI: 10.1007/s12031-019-01289-w -
World Journal of Cardiology Jun 2020Cardiac catheterization is among the most performed medical procedures in the modern era. There were sporadic reports indicating that cardiac arrhythmias are common...
BACKGROUND
Cardiac catheterization is among the most performed medical procedures in the modern era. There were sporadic reports indicating that cardiac arrhythmias are common during cardiac catheterization, and there are risks of developing serious and potentially life-threatening arrhythmias, such as sustained ventricular tachycardia (VT), ventricular fibrillation (VF) and high-grade conduction disturbances such as complete heart block (CHB), requiring immediate interventions. However, there is lack of systematic overview of these conditions.
AIM
To systematically review existing literature and gain better understanding of the incidence of cardiac arrhythmias during cardiac catheterization, and their impact on outcomes, as well as potential approaches to minimize this risk.
METHODS
We applied a combination of terms potentially used in reports describing various cardiac arrhythmias during common cardiac catheterization procedures to systematically search PubMed, EMBASE and Cochrane databases, as well as references of full-length articles.
RESULTS
During right heart catheterization (RHC), the incidence of atrial arrhythmias (premature atrial complexes, atrial fibrillation and flutter) was low (< 1%); these arrhythmias were usually transient and self-limited. RHC associated with the development of a new RBBB at a rate of 0.1%-0.3% in individuals with normal conduction system but up to 6.3% in individuals with pre-existing left bundle branch block. These patients may require temporary pacing due to transient CHB. Isolated premature ventricular complexes or non-sustained VT are common during RHC (up to 20% of cases). Sustained ventricular arrhythmias (VT and/or VF) requiring either withdrawal of catheter or cardioversion occurred infrequently (1%-1.3%). During left heart catheterizations (LHC), the incidence of ventricular arrhythmias has declined significantly over the last few decades, from 1.1% historically to 0.1% currently. The overall reported rate of VT/VF in diagnostic LHC and coronary angiography is 0.8%. The risk of VT/VF was higher during percutaneous coronary interventions for stable coronary artery disease (1.1%) and even higher for patients with acute myocardial infarctions (4.1%-4.3%). Intravenous adenosine and papaverine bolus for fractional flow reserve measurement, as well as intracoronary imaging using optical coherence tomography have been reported to induce VF. Although uncommon, LHC and coronary angiography were also reported to induce conduction disturbances including CHB.
CONCLUSION
Cardiac arrhythmias are common and potentially serious complications of cardiac catheterization procedures, and it demands constant vigilance and readiness to intervene during procedures.
PubMed: 32774779
DOI: 10.4330/wjc.v12.i6.269 -
Experimental Eye Research Nov 2021Increasing the level of cyclic adenosine 3, 5'-monophosphate is an important mechanism for axon outgrowth and recovery of central nervous system function. This study...
Increasing the level of cyclic adenosine 3, 5'-monophosphate is an important mechanism for axon outgrowth and recovery of central nervous system function. This study aimed to investigate the effects of papaverine, a non-specific phosphodiesterase inhibitor, on axon outgrowth of primary retinal ganglion cells from Sprague Dawley rats. Experiments were performed on primary retinal ganglion cells extracted from Sprague Dawley rat pups within 48-72 h of birth. At 24 h after seeding, immunofluorescence was used to identify and calculate the purity of retinal ganglion cells isolated by an improved two-step immunopanning method developed by author Sujia Ma. The effects of a range of papaverine concentrations on axon outgrowth of primary retinal ganglion cells cultures were observed by immunofluorescence and measured by ImageJ software at three different time points: 24, 48, and 72 h. The ability of papaverine to enable retinal ganglion cells to overcome the inhibitory effects of glial scar component chondroitin sulfate proteoglycans was examined using chondroitin sulfate proteoglycans-coated culture plates. Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt, a blocking agent of cyclic adenosine 3, 5'-monophosphate, and dibutyryl cyclic adenosine 3, 5'-monophosphate, an analogue of cyclic adenosine 3, 5'-monophosphate, were used to explore the mechanism of papaverine in promoting retinal ganglion cells axon outgrowth. Our study shows 2 μg/mL papaverine concentration significantly promoted axon outgrowth in primary retinal ganglion cells and restored axon outgrowth of these cells on chondroitin sulfate proteoglycans. Axon outgrowth was blocked by Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt and obviously promoted by dibutyryl cyclic adenosine 3, 5'-monophosphate. Our study is the first to describe the use of papaverine to promote axon outgrowth of retinal ganglion cells. These results may help to expand the application of papaverine, and they provide a cytological basis for papaverine in the treatment of optic nerve injury caused by glaucoma and other diseases.
Topics: Animals; Cells, Cultured; Disease Models, Animal; Glaucoma; Nerve Regeneration; Neuronal Outgrowth; Papaverine; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells
PubMed: 34687724
DOI: 10.1016/j.exer.2021.108797 -
Andrology Jan 2017Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is...
Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is well-known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. This study was undertaken to characterize cAMP-PDE activity in bovine spermatozoa. Total cAMP-PDE activity in cauda epididymal and ejaculated spermatozoa was 543.2 ± 49.5 and 1252.6 ± 86.5 fmoles/min/10 spermatozoa, respectively. Using different family-specific PDE inhibitors, we showed that in cauda epididymal and ejaculated spermatozoa, the major cAMP-PDE activity was papaverine-sensitive (44.5% and 57.5%, respectively, at 400 nm, papaverine is a specific inhibitor of the PDE10 family). These data are supporting the functional presence of PDE10 in bovine spermatozoa and were further confirmed by western blot to be PDE10A. Using immunocytochemistry, we showed immunoreactive signal for PDE10A present on the post-acrosomal region of the head and on the flagella of ejaculated spermatozoa. Using papaverine, we showed that it promotes tyrosine phosphorylation of sperm proteins, phosphorylation of Erk1 and Erk2, and Ca release from Ca store. These results suggest that PDE10 is functionally present in bovine spermatozoa and is affecting different molecular events involved in capacitation, most probably by cAMP local regulation.
Topics: Acrosome Reaction; Animals; Calcium; Cattle; Epididymis; Male; Papaverine; Phosphoric Diester Hydrolases; Phosphorylation; Signal Transduction; Spermatozoa
PubMed: 27860455
DOI: 10.1111/andr.12290 -
The British Journal of Radiology Nov 2020Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental... (Review)
Review
Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental stresses like hypoxia and nutrient deprivation. Radiation is extensively applied in a large number of cancer treatment protocols but despite its curative potential, radiation resistance and treatment failures pose a serious problem. Metabolic control of DNA integrity and genomic stability can occur through multiple processes, encompassing cell cycle regulation, nucleotide synthesis, epigenetic regulation of gene activity, and antioxidant defenses. Given the important role of metabolic pathways in oxidative damage responses, it is necessary to assess the potential for tumor-specific radiosensitization by novel metabolism-targeted therapies. Additionally, there are opportunities to identify molecular and functional biomarkers of vulnerabilities to combination treatments, which could then inform clinical decisions. Here, we present a curated list of metabolic pathways in the context of ionizing radiation responses. Glutamine metabolism influences DNA damage responses by mechanisms such as synthesis of nucleotides for DNA repair or of glutathione for ROS detoxification. Repurposed oxygen consumption inhibitors have shown promising radiosensitizing activity against murine model tumors and are now in clinical trials. Production of 2-hydroxy glutarate by isocitrate dehydrogenase1/2 neomorphic oncogenic mutants interferes with the function of α-ketoglutarate-dependent enzymes and modulates Ataxia Telangiectasia Mutated (ATM) signaling and glutathione pools. Radiation-induced oxidative damage to membrane phospholipids promotes ferroptotic cell loss and cooperates with immunotherapies to improve tumor control. In summary, there are opportunities to enhance the efficacy of radiotherapy by exploiting cell-inherent vulnerabilities and dynamic microenvironmental components of the tumor.
Topics: Adaptation, Physiological; Animals; Ataxia Telangiectasia Mutated Proteins; DNA; DNA Damage; DNA Repair; Genomic Instability; Glutamine; Glutarates; Glutathione; Humans; Immunotherapy; Isocitrate Dehydrogenase; Ketoglutaric Acids; Lipid Peroxidation; Mice; Neoplasms; Nucleotides; Oxygen Consumption; Phospholipids; Radiation Tolerance; Radiation-Sensitizing Agents; Reactive Oxygen Species; Stress, Physiological; Treatment Outcome; Tumor Microenvironment
PubMed: 32462882
DOI: 10.1259/bjr.20200067 -
Journal of Interventional Cardiology 2020The saline-induced distal coronary pressure/aortic pressure ratio predicted fractional flow reserve (FFR). The resting full-cycle ratio (RFR) represents the maximal...
BACKGROUND
The saline-induced distal coronary pressure/aortic pressure ratio predicted fractional flow reserve (FFR). The resting full-cycle ratio (RFR) represents the maximal relative pressure difference in a cardiac cycle. Therefore, the present study aimed to compare the results of saline-induced RFR (sRFR) with FFR.
METHODS
Seventy consecutive lesions with only moderate stenosis were included. The FFR, RFR, and sRFR values were compared. The sRFR was assessed using an intracoronary bolus infusion of saline (2 mL/s) for five heartbeats. The FFR was obtained after an intravenous injection of papaverine.
RESULTS
Overall, the FFR, sRFR, and RFR values were 0.78 ± 0.12, 0.79 ± 0.13, and 0.83 ± 0.14, respectively. With regard to anatomical morphology were 40, 18, and 12 cases of focal, diffuse, and tandem lesion. There was a significant correlation between the sRFR and FFR ( = 0.96, < 0.01). There were also significant correlations between the sRFR and FFR in the left coronary and right coronary artery ( = 0.95, < 0.01 and = 0.98, < 0.01). Furthermore, significant correlations between sRFR and FFR were observed in not only focal but also in nonfocal lesion including tandem and diffuse lesions ( = 0.93, < 0.01 and = 0.97, < 0.01). A close agreement on FFR and sRFR was shown using the Bland-Altman analysis (95% CI of agreement: -0.08-0.07). In the receiver operating characteristic curve analysis, the cutoff value of sRFR to predict an FFR of 0.80 was 0.81 (area under curve, 0.97; sensitivity 90.6%; and specificity 98.2%).
CONCLUSION
The sRFR can accurately and safely predict the FFR and might be effective for diagnosing ischemia.
Topics: Aged; Aged, 80 and over; Arterial Pressure; Cardiac Catheterization; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Female; Fractional Flow Reserve, Myocardial; Hemodynamics; Humans; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Severity of Illness Index
PubMed: 32327943
DOI: 10.1155/2020/5787439 -
Acta Cirurgica Brasileira 2021This study assessed the regeneration potential of mesenchymal stem cells (MSC) from adipose tissue associated with platelet-rich plasma (PRP) in bone regeneration.
PURPOSE
This study assessed the regeneration potential of mesenchymal stem cells (MSC) from adipose tissue associated with platelet-rich plasma (PRP) in bone regeneration.
METHODS
Thirty Wistar rats (Rattus norvegicus albinos) were divided into five groups (according to the grafting material and time to euthanasia): (1) autograft - 14 days (control), (2) autograft - 28 days (control), (3) MSC + PRP - 14 days, (4) MSC + PRP + papaverine - 14 days and (5) MSC + PRP + papaverine - 28 days. After euthanasia, the graft was removed and histological slides were prepared. They were assessed by a blinded pathologist using a previously published histological scale as parameter.
RESULTS
There was some degree of neoformed bone trabeculae (NBT) in 93.3% of the samples, as well as osteoblastic activity (OA). The autograft groups (14 and 28 days) had higher levels in the formation of bone trabeculae. Nonparametric data were analyzed using the Wilcoxon-Mann-Whitney test and proved not to be statistically significant at p < 0.05.
CONCLUSIONS
Experimental parietal bone reconstruction, combining MSC, PRP and papaverine presented regeneration in all groups with no significant difference among them.
Topics: Animals; Bone Regeneration; Mesenchymal Stem Cells; Parietal Bone; Platelet-Rich Plasma; Rats; Rats, Wistar
PubMed: 33503214
DOI: 10.1590/ACB351201 -
Current Research in Pharmacology and... 2024Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The...
Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The Farnesoid X receptor (FXR) is a vital target for the therapy of cholestasis since it regulates BA homeostasis. Despite the discovery of multiple active FXR agonists, there are still no effective treatments for cholestasis. Papaverine is identified as an FXR agonist.This study investigates papaverine's efficacy and probable mechanism in protecting against alpha naphthylisothiocyanate (ANIT) induced cholestasis. Thirty male albino rats were divided into three groups, each with ten rats. Group I (control) rats were administered 1 mL/kg corn oil 48 h before sacrifice; group II rats were orally administered 100 mg/kg ANIT. Group III received a 200 mg/kg dosage of papaverine over seven consecutive days. A single dose of ANIT at a concentration of 100 mg/kg was orally administered on the fifth day; group II and III animals were euthanized 48 h after inducing cholestasis, and serum concentrations of liver function tests and total bile acid (TBA) were measured. Besides measuring the inflammatory mediator's tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1β), antioxidant markers such as superoxide dismutase (SOD) and glutathione (GSH) were also assessed. The findings indicated the enhancement in the liver function test and total bile acids, as well as in liver histology; papaverine significantly lowered TNF-α and IL-1β while SOD and GSH significantly increased. Additionally, papaverine upregulates gene expression, bile salt export pump (), small heterodimer partner (), hepatocyte nuclear factor 1α (), nuclear factor erythroid 2-related factor (), heme oxygenase (), NAD(P)H quinone oxidoreductase 1 (). Furthermore, papaverine increased protein expressions of Sirtuin1. (SIRT 1), FXR, HO-1, and BSEP levels in the rats' livers. The protective effects of papaverine may be attributed to the activation of FXR signaling pathways. These findings revealed that papaverine protects against ANIT-induced Cholestasis.
PubMed: 38322817
DOI: 10.1016/j.crphar.2024.100177