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Medicine and Pharmacy Reports Jan 2024Vascular reactivity may be influenced by the dysfunction of the perivascular adipose tissue (PVAT) that occurs after a prolonged high fat diet (HFD).
BACKGROUND
Vascular reactivity may be influenced by the dysfunction of the perivascular adipose tissue (PVAT) that occurs after a prolonged high fat diet (HFD).
AIM
The aim of this study was to investigate the vascular responses in rats with prolonged HFD after the administration of L. extract as a simple solution or as a reducing agent for gold nanoparticles (AuNPs).
METHODS
Sprague-Dawley adult female rats (21 animals) were randomly allocated into three groups (n=7) and received for 9 months hyperlipid diet, the last month with treatment administered through oral gavage, 0.5 mL/day of solution as follows: HFD group - 0.9% saline solution, HFD+CM group - L. extract (0.158 mg/mL polyphenols), HFD+AuNPsCM group - gold nanoparticles phytoreduced with L. extract (AuNPsCM, 260 μg Au/kg/day). The Control group of rats (n=7) was fed with standard diet and in the last month received 0.9% saline solution as treatment. At the end of the experiment, the rats' descending aortas were collected and were used to investigate the aorta wall responses to vasoconstrictor (phenylephrine) and vasodilator (acetylcholine) substances added in tissue bath.
RESULTS
AuNPsCM administration, compared to Control and HFD groups, increased the contraction and reduced the relaxation in aorta rings of rats with prolonged high-fat diet. The simple solution of L. extract produced contractile responses similar to those recorded in the Control group, at lower levels than in HFD group, and relaxation responses significantly decreased in comparison with Control group and significant increased when compared to HFD group.
CONCLUSIONS
L. extract administered as simple solution improved the aorta functions, while AuNPsCM solution enhanced the existed aorta wall modifications occurred after prolonged HFD, altering the vessel wall responses.
PubMed: 38344328
DOI: 10.15386/mpr-2659 -
Acta Pharmaceutica Sinica. B Feb 2024Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely...
Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with , and validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells intracellular PI3K/Akt signaling pathway, alleviate 1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.
PubMed: 38322337
DOI: 10.1016/j.apsb.2023.10.022 -
BMC Chemistry Feb 2024A facile, sensitive, accurate and green spectrofluorimetric method was evolved for the assay of ciprofloxacin hydrochloride (CFX) and phenylephrine hydrochloride (PLN)...
Eco-friendly, sensitive and inventive first derivative synchronous spectrofluorimetric determination of ciprofloxacin and phenylephrine in their pure form, single and combined eye drops.
A facile, sensitive, accurate and green spectrofluorimetric method was evolved for the assay of ciprofloxacin hydrochloride (CFX) and phenylephrine hydrochloride (PLN) in their co-formulated eye drops with their challengeable ratio of 30:1 for CFX and PLN, respectively. Such drops are clinically used for the treatment of eye bacterial infections. They relieve the symptoms of infection by stopping further growth of the causative microorganisms. The assay principle based on first-order synchronous spectrofluorometric scan using Δ λ = 40 nm in which PLN peak amplitudes were recorded at 283.4 nm, meanwhile CFX was measured at 326.2 nm in the same scans. The calibration curves were linear within the concentration ranges: 0.02-0.5 µg/mL and 0.5-5.0 µg/mL for PLN and CFX, respectively. The method validation was confirmed following the International Conference of Harmonization (ICH) Guidelines. This suggested method was the first one that described simultaneous analysis of PLN and CFX by a spectrofluorimetric technique. In this method, green analytical procedures were implemented to lessen occupational and environmental perils and method greenness was assessed by four assessment tools. GAPI, NEMI, AGREE and Analytical eco-scale were applied to this study and it was deduced from their results that the method had high degree of greenness as it fulfilled all requirements of GAPI, NEMI pictograms and it had high scores of analytical eco scale (97) and AGREE methods (0.82). Subsequently, it was successfully applied to assay both drugs in pure forms, pharmaceutical single and co-formulated eye drops.
PubMed: 38317259
DOI: 10.1186/s13065-024-01131-4 -
Scientific Reports Jan 2024A posterior approach is recommended for the correction of mild to moderate upper eyelid ptosis in adults. The aim of this study is to propose a new algorithm that helps...
A posterior approach is recommended for the correction of mild to moderate upper eyelid ptosis in adults. The aim of this study is to propose a new algorithm that helps to predict outcomes in the transconjunctival correction of moderate to severe blepharoptosis. This study included adult patients with moderate to severe upper eyelid ptosis treated between 2019 and 2021. Patients meeting inclusion criteria underwent ptosis correction through a posterior approach using an algorithm: 4 mm Mueller's muscle transconjunctival resection to correct 1 mm ptosis (depending on a test with 10% phenylephrine: 3-12 mm) ± tarsal plate resection: 1 mm for every 1 mm of residual ptosis after phenylephrine test, but leaving a minimum of 4 mm upper tarsus intact. Outcomes were ovserved within at least 6-months. Outcomes were assessed based on pre- and postoperative MRD1 changes, inter-eyelid height symmetry, cosmetic effect, and complications. Outcomes of 118 procedures in 81 patients (average age 69, range: 47-87) were analyzed. MRD1 changes were statistically significant, from 0.2 ± 1.6 mm before to 4.1 ± 1 mm after surgery. The function of the levator palpebrae superioris muscle was 10.2 ± 3.4 (range 5-17) mm. Upper eyelid lifted by an average of 1.8 ± 0.7 (range 0-3) mm after the instillation of 10% phenylephrine eyedrops. An average of 8.5 ± 0.8 (range 8-10) mm of conjunctiva and Mueller's muscle and 2.2 ± 0.9 (range 1-5) mm of the tarsal plate were resected during the procedure. Inter-eyelid height symmetry within 1 mm was achieved in 95% of outcomes. The algorithm introduced in this study appears to be useful to achieve repeatable satisfactory outcomes in the transconjunctival correction of moderate to severe upper eyelid ptosis in adults with at least "fair" levator function.
Topics: Adult; Humans; Aged; Blepharoptosis; Blepharoplasty; Retrospective Studies; Eyelids; Phenylephrine; Algorithms
PubMed: 38297133
DOI: 10.1038/s41598-024-52990-9 -
ACS Omega Jan 2024(Hausskn.) Pugsley (FIP), a member of the Papaveraceae family, has a documented history of use in traditional medicine to treat cardiovascular ailments, particularly...
(Hausskn.) Pugsley (FIP), a member of the Papaveraceae family, has a documented history of use in traditional medicine to treat cardiovascular ailments, particularly hypertension, and has shown substantial therapeutic efficacy among native cultures worldwide. However, the identification of bioactive compounds and the mechanism of hypotensive effect with the cardioprotective potential investigations are yet to be determined. The study aimed to identify bioactive compounds, explore the hypotensive mechanism and cardioprotective potential, and assess the safety of (Hausskn.) Pugsley hydromethanolic extract (Fip.Cr). LC ESI-MS/MS analysis was performed to identify the bioactive compounds. In vitro experiments were conducted on isolated rat aorta and atria, and an invasive BP measurement model was used. Acute and subacute toxicities were assessed for 14 and 28 days, respectively. Isoproterenol (ISO) was used to develop the rats' myocardial infarction damage model. The mRNA levels of NLRP3 inflammasome and the abundance level of Firmicutes and Lactobacillus were measured by qRT-PCR. The hypotensive effect of FIP bioactive compounds was also investigated using in silico methods. Fip. Cr LC ESI-MS/MS analysis discovered 33 bioactive compounds, including alkaloids and flavonoids. In isolated rat aorta, Fip.Cr reversed contractions induced by K (80 mM), demonstrating a calcium entry-blocking function, and had a vasorelaxant impact on phenylephrine (PE) (1 μM)-induced contractions unaffected by L-NAME, ruling out endothelial NO participation. Fip.Cr caused negative chronotropic and inotropic effects in isolated rat atria unaffected by atropine pretreatment, eliminating cardiac muscarinic receptor involvement. Safety evaluation showed no major adverse effects. In vivo, invasive BP measurement demonstrated a hypotensive effect comparable to verapamil. Fip.Cr protected the rats from ISO-induced MI interventions significantly in biometrical and cardiac serum biochemical indicators and histological examinations by reducing inflammation via inhibiting NLRP3 inflammasome and elevating Firmicutes and Lactobacillus levels. The network pharmacology study revealed that the FIP hypotensive mechanism might involve MMP9, JAK2, HMOX1, NOS2, NOS3, TEK, SERPINE1, CCL2, and VEGFA. The molecular docking study revealed that FIP bioactive compounds docked better with CAC1C_ HUMAN than verapamil. These findings demonstrated that Fip.Cr's hypotensive mechanism may include calcium channel blocker activity. Fip.Cr ameliorated ISO-induced myocardial infarction in rats by attenuating inflammation, which might be via inhibiting NLRP3 inflammasome and may prove beneficial for treating MI.
PubMed: 38284069
DOI: 10.1021/acsomega.3c07655 -
Circulation Research Feb 2024The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors....
BACKGROUND
The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear.
METHODS
Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice.
RESULTS
(1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival.
CONCLUSIONS
Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
Topics: Mice; Rats; Animals; Proteasome Endopeptidase Complex; Cyclic AMP-Dependent Protein Kinases; Glycogen Synthase Kinase 3 beta; Cardiomegaly; Myocytes, Cardiac; Mice, Transgenic; Peptides; Mammals
PubMed: 38275112
DOI: 10.1161/CIRCRESAHA.123.322729 -
Frontiers in Pharmacology 2023The infusion of phenylephrine to prevent spinal-induced hypotension (SIH) in cesarean delivery may decrease the rostral spread of a spinal local anesthetic. We...
The infusion of phenylephrine to prevent spinal-induced hypotension (SIH) in cesarean delivery may decrease the rostral spread of a spinal local anesthetic. We hypothesized that infusion of norepinephrine may decrease the rostral spread of spinal anesthesia, similar to that caused by phenylephrine. The aim of this study was to compare the block height of spinal anesthesia in the presence or absence of norepinephrine infusion administered to prevent SIH during cesarean delivery. Eighty patients were enrolled and allocated into groups receiving a norepinephrine infusion (group N) or saline infusion (group C). After intrathecal injection of hyperbaric bupivacaine 10 mg, the block height for cold and pinprick sensation was checked 10 and 20 min after the injection. The demographic characteristics, spinal anesthesia, side effects, and neonatal outcomes were also recorded. The block height for cold and pinprick sensation was similar between the two groups, although the incidence of hypotension was significantly lower ( 0.00) in group N than in group C. Systolic blood pressure was also more stable in group N than in group C, with the incidence of interventions being significantly lower in group N. There was no significant difference in patient satisfaction between the two groups. Evidence from this study suggested that prophylactic norepinephrine infusion does not reduce the rostral spread of spinal anesthesia in pregnancy. We suggest that it is not necessary to increase the dose of an intrathecal local anesthetic for cesarean delivery when prophylactic norepinephrine is administered. : https://www.chictr.org.cn/bin/project/edit?pid=152899, identifier [ChiCTR2200057439].
PubMed: 38264521
DOI: 10.3389/fphar.2023.1340452 -
International Journal of Molecular... Jan 2024We studied whether the function of presynaptic inhibitory cannabinoid CB receptors on the sympathetic nerve fibres innervating resistance vessels is increased in...
We studied whether the function of presynaptic inhibitory cannabinoid CB receptors on the sympathetic nerve fibres innervating resistance vessels is increased in spontaneously hypertensive rats (SHR) like in deoxycorticosterone (DOCA)-salt hypertension. An increase in diastolic blood pressure (DBP) was induced by electrical stimulation of the preganglionic sympathetic neurons or by phenylephrine injection in pithed SHR and normotensive Wistar-Kyoto rats (WKY). The electrically (but not the phenylephrine) induced increase in DBP was inhibited by the cannabinoid receptor agonist CP55940, similarly in both groups, and by the endocannabinoid reuptake inhibitor AM404 in SHR only. The effect of CP55940 was abolished/reduced by the CB receptor antagonist AM251 (in both groups) and in WKY by endocannabinoid degradation blockade, i.e., the monoacylglycerol lipase (MAGL) inhibitor MJN110 and the dual fatty acid amide hydrolase (FAAH)/MAGL inhibitor JZL195 but not the FAAH inhibitor URB597. MJN110 and JZL195 tended to enhance the effect of CP55940 in SHR. In conclusion, the function of presynaptic inhibitory CB receptors depends on the hypertension model. Although no differences occurred between SHR and WKY under basal experimental conditions, the CB receptor function was better preserved in SHR when the endocannabinoid tone was increased by the inhibition of MAGL or the endocannabinoid transporter.
Topics: Rats; Animals; Rats, Inbred WKY; Endocannabinoids; Cannabinoids; Rats, Inbred SHR; Hypertension; Phenylephrine; Carbamates; Cyclohexanols; Piperazines; Succinimides
PubMed: 38255931
DOI: 10.3390/ijms25020858 -
Hypertension (Dallas, Tex. : 1979) Apr 2024Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance...
BACKGROUND
Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance arteries, declining NO enhances vascular smooth muscle (VSM) reactivity partly by enabling rapid depolarizing Ca-based spikes that underlie vasospasm. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is metabolized by DDAH1 (dimethylarginine dimethylaminohydrolase 1) and elevated in cardiovascular disease. We hypothesized ADMA might enable VSM spikes and vasospasm by reducing NO bioavailability, which is opposed by DDAH1 activity and L-arginine.
METHODS
Rat isolated small mesenteric arteries and myogenic rat-isolated intraseptal coronary arteries (RCA) were studied using myography, VSM intracellular recording, Ca imaging, and DDAH1 immunolabeling. Exogenous ADMA was used to inhibit NO synthase and a selective DDAH1 inhibitor, N-(2-methoxyethyl) arginine, to assess the functional impact of ADMA metabolism.
RESULTS
ADMA enhanced rat-isolated small mesenteric arteries vasoreactivity to the α-adrenoceptor agonist, phenylephrine by enabling T-type voltage-gated calcium channel-dependent depolarizing spikes. However, some endothelium-dependent NO-vasorelaxation remained, which was sensitive to DDAH1-inhibition with N-(2-methoxyethyl) arginine. In myogenically active RCA, ADMA alone stimulated depolarizing Ca spikes and marked vasoconstriction, while NO vasorelaxation was abolished. DDAH1 expression was greater in rat-isolated small mesenteric arteries endothelium compared with RCA, but low in VSM of both arteries. L-arginine prevented depolarizing spikes and protected NO-vasorelaxation in rat-isolated small mesenteric artery and RCA.
CONCLUSIONS
ADMA increases VSM electrical excitability enhancing vasoreactivity. Endothelial DDAH1 reduces this effect, and low levels of DDAH1 in RCAs may render them susceptible to endothelial dysfunction contributing to vasospasm, changes opposed by L-arginine.
Topics: Rats; Animals; Cardiovascular Diseases; Coronary Vessels; Arginine; Nitric Oxide Synthase; Amidohydrolases; Nitric Oxide
PubMed: 38226470
DOI: 10.1161/HYPERTENSIONAHA.123.22454 -
Mikrochimica Acta Jan 2024The combination of multi-walled carbon nanotubes (MWCNT) and carbon black (CB) is presented to produce a high-performance electrically conductive recycled additive...
Multi-walled carbon nanotubes/carbon black/rPLA for high-performance conductive additive manufacturing filament and the simultaneous detection of acetaminophen and phenylephrine.
The combination of multi-walled carbon nanotubes (MWCNT) and carbon black (CB) is presented to produce a high-performance electrically conductive recycled additive manufacturing filament. The filament and subsequent additively manufactured electrodes were characterised by TGA, XPS, Raman, and SEM and showed excellent low-temperature flexibility. The MWCNT/CB filament exhibited an improved electrochemical performance compared to an identical in-house produced bespoke filament using only CB. A heterogeneous electrochemical rate constant, [Formula: see text] of 1.71 (± 0.19) × 10 cm s was obtained, showing an almost six times improvement over the commonly used commercial conductive CB/PLA. The filament was successfully tested for the simultaneous determination of acetaminophen and phenylephrine, producing linear ranges of 5-60 and 5-200 μM, sensitivities of 0.05 μA μM and 0.14 μA μM, and limits of detection of 0.04 μM and 0.38 μM, respectively. A print-at-home device is presented where a removable lid comprised of rPLA can be placed onto a drinking vessel and the working, counter, and reference components made from our bespoke MWCNT/CB filament. The print-at-home device was successfully used to determine both compounds within real pharmaceutical products, with recoveries between 87 and 120% over a range of three real samples. This work paves the way for fabricating new highly conductive filaments using a combination of carbon materials with different morphologies and physicochemical properties and their application to produce additively manufactured electrodes with greatly improved electrochemical performance.
Topics: Acetaminophen; Nanotubes, Carbon; Soot; Phenylephrine; Electrochemical Techniques
PubMed: 38225436
DOI: 10.1007/s00604-023-06175-2