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Current Issues in Molecular Biology Jan 2022Pacliatxel is a taxol-based chemotherapeutic drug that is widely used to treat cancer. However, it can also induce peripheral neuropathy, which limits its use. Although...
Pacliatxel is a taxol-based chemotherapeutic drug that is widely used to treat cancer. However, it can also induce peripheral neuropathy, which limits its use. Although several drugs are prescribed to attenuate neuropathies, no optimal treatment is available. Thus, in our study, we analyzed whether SH003 and its sub-components could alleviate paclitaxel-induced neuropathic pain. Multiple paclitaxel injections (cumulative dose 8 mg/kg, i.p.) induced cold and mechanical allodynia from day 10 to day 21 after the first injection in mice. Oral administration of SH003, an herbal mixture extract of , , and Maximowicz (Tk), dose-dependently attenuated both allodynia. However, when administered separately only Tk decreased both allodynia. The effect of Tk was shown to be mediated by the spinal noradrenergic system as intrathecal pretreatment with α- and α-adrenergic-receptor antagonists (prazosin and idazoxan), but not 5-HT, and 5-HT-receptor antagonists (methysergide and MDL-72222) blocked the effect of Tk. The spinal noradrenaline levels were also upregulated. Among the phytochemicals of Tk, cucurbitacin D was shown to play a major role, as 0.025 mg/kg (i.p.) of cucurbitacin D alleviated allodynia similar to 500 mg/kg of SH003. These results suggest that Tk should be considered when treating paclitaxel-induced neuropathic pain.
PubMed: 35723335
DOI: 10.3390/cimb44020050 -
Frontiers in Pharmacology 2021(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the...
Aqueous Tuber Extracts of (Kotschy ex Schweinf.) Torre and Hillc. (Fabaceae). Possess Significant Antidiarrheal Activity and Spasmolytic Effect Possibly Mediated by Modulation of Nitrous Oxide System, Voltage-Gated Calcium Channels, and Muscarinic Receptors.
(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the putative mechanism (s) of action using Sprague-Dawley rats and New Zealand white rabbits respectively. The antidiarrheal effects of the extract were evaluated in castor oil-induced diarrhea, the castor oil-induced enteropooling, and phenol red gastric motility tests. On the other hand, isolated rabbit's jejunal segments were used to evaluate the spasmolytic effect of TFG on spontaneous contraction, in acetylcholine-induced contraction, in presence of 80mMK, calcium chloride-induced contraction as well as in presence of the following antagonists: naloxone, methylene blue, L-NAME, prazosin, and propranolol in the studies. The data were express as Mean ± S.E.M and analyzed by one-way ANOVA and Tukey's post hoc test in cases of significance which was set at < 0.05. The extract was phytochemically characterized using Liquid chromatography Mass spectroscopy (LC-MS).The extract possessed significant inhibitory effect in the experiments. The extract exhibited significant spasmolytic effect on both spontaneous contraction and in jejunal segment pre-contracted acetylcholine as well as in presence of 80mMK solution. It also attenuated the spasmogenic effect of various concentration of calcium chloride. The extract's spasmolytic effect was, however, significantly attenuated in presence of several antagonists (methylene blue and L-NAME) but the adrenergic blockers (prazosin and propranolol) had no significant effect in the LC-MS identified thirty compounds where Proathocyanidin (11.54%), Syringic acid (7.30%), and 4-Hydroxybenzoic acid (6.19%) had the highest percentage abundance. In conclusion, the results obtained in this study partially validate the traditional uses of the tubers of this plant species as an antidiarrheal. These antidiarrheal effects are probably mediated via modulation of nitrous oxide pathway, voltage gated calcium channels, and muscarinic receptors.
PubMed: 33796023
DOI: 10.3389/fphar.2021.636879 -
Biology Sep 2022Quorum sensing (QS) controls the production of several bacterial virulence factors. There is accumulative evidence to support that targeting QS can ensure a significant...
Quorum sensing (QS) controls the production of several bacterial virulence factors. There is accumulative evidence to support that targeting QS can ensure a significant diminishing of bacterial virulence. Lessening bacterial virulence has been approved as an efficient strategy to overcome the development of antimicrobial resistance. The current study aimed to assess the anti-QS and anti-virulence activities of α-adrenoreceptor prazosin against three virulent Gram-negative bacteria , , and . The evaluation of anti-QS was carried out on a series of in vitro experiments, while the anti-virulence activities of prazosin were tested in an in vivo animal model. The prazosin anti-QS activity was assessed on the production of QS-controlled pigment violacein and the expression of QS-encoding genes in . In vitro tests were performed to evaluate the prazosin effects on biofilm formation and production of extracellular enzymes by , , and . A protective assay was conducted to evaluate the in vivo anti-virulence activity of prazosin against , , and . Moreover, precise in silico molecular docking was performed to test the prazosin affinity to different QS receptors. The results revealed that prazosin significantly decreased the production of violacein and the virulent enzymes, protease and hemolysins, in the tested strains. Prazosin significantly diminished biofilm formation in vitro and bacterial virulence in vivo. The prazosin anti-QS activity was proven by its downregulation of QS-encoding genes and its obvious binding affinity to QS receptors. In conclusion, prazosin could be considered an efficient anti-virulence agent to be used as an adjuvant to antibiotics, however, it requires further pharmacological evaluations prior to clinical application.
PubMed: 36138828
DOI: 10.3390/biology11091349 -
Case Reports in Psychiatry 2022Posttraumatic stress disorder (PTSD) is a debilitating stress disorder occurring in the context of a traumatic event and is characterized by intrusive and avoidance...
Posttraumatic stress disorder (PTSD) is a debilitating stress disorder occurring in the context of a traumatic event and is characterized by intrusive and avoidance symptoms, negative alterations in cognition and mood, and arousal and reactivity changes. Despite its representation throughout literature, the pathophysiology of PTSD remains incompletely understood, thus contributing to broad, variable, and at times, experimental treatment options. The authors present the first documented case of the rapid and successful management of PTSD using valproic acid and twice daily dosing of prazosin aimed at targeting symptoms of hyperarousal and both daily and nightly intrusive symptoms of flashbacks and nightmares, respectively. The authors also discuss postulations of the underlying mechanisms of action responsible for such symptom alleviation. Further investigation is needed to expand upon our knowledge of the use of such agents in the treatment of PTSD to improve upon existing clinical guidelines, especially in the acute setting, thus providing better overall prognosis.
PubMed: 35966042
DOI: 10.1155/2022/1223292 -
BMJ Case Reports Mar 2020Paraganglioma of the bladder is a rare tumour accounting for less than 0.06% of all urinary bladder tumours and has varied presentations. It may present with clinical...
Paraganglioma of the bladder is a rare tumour accounting for less than 0.06% of all urinary bladder tumours and has varied presentations. It may present with clinical symptoms of phaeochromocytoma, may be non-functioning and asymptomatic or may present with haematuria. Hence, paragangliomas are occasionally misdiagnosed, and this results in unanticipated intraoperative hypertensive crisis. We present the case of a 44-year-old woman with urinary bladder paraganglioma who presented with young onset hypertension, recurrent micturition syncope with prior history of coronary artery disease and stroke. She was stabilised preoperatively with alpha blocking agents and subsequently underwent successful transurethral resection of the same.
Topics: 3-Iodobenzylguanidine; Adrenergic alpha-1 Receptor Antagonists; Adult; Diagnosis, Differential; Diagnostic Errors; Female; Humans; Hypertension; Normetanephrine; Paraganglioma; Prazosin; Preoperative Care; Syncope; Tomography, X-Ray Computed; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 32169989
DOI: 10.1136/bcr-2019-233556 -
BMC Anesthesiology Sep 2019The α-receptor agonist dexmedetomidine (Dex) has been shown to produce sedative and analgesic effects not only with systemic administration but also when administered...
BACKGROUND
The α-receptor agonist dexmedetomidine (Dex) has been shown to produce sedative and analgesic effects not only with systemic administration but also when administered in the extradural space and around peripheral nerves. The effects and mechanism of action of Dex on pulmonary arteries, however, have not been determined. This study therefore aimed to investigate the effect of Dex on pulmonary arterial vascular smooth muscle by evaluating changes in isometric contraction tension. We then attempted to determine the effects of Dex on depolarization stimulation and receptor stimulation.
METHODS
Endothelium-denuded porcine pulmonary arteries were sliced into 2- to 3-mm rings. We then exposed them to certain substances at various concentrations under different conditions of baseline stimulation (with KCl, adrenaline, caffeine, or histamine) and to α-receptor stimulants or antagonists, or α-receptor antagonists (imidazoline, yohimbine, rauwolscine, prazosin), and different conditions of Ca depletion of the intracellular reservoir or extracellular stores. We measured the changes in isometric contraction tension with each addition or change in conditions.
RESULTS
Dex enhanced the contraction induced by high-concentration KCl stimulation. Dex-induced enhancement of contraction induced by high-concentration KCl was completely suppressed by yohimbine and rauwolscine, which are α-receptor antagonists, but not by prazosin. Dex, imidazoline, yohimbine, and rauwolscine reduced the increases in contraction tension induced by the receptor stimulant adrenaline. Dex suppressed the adrenaline-induced increases in contraction tension after depletion of the Ca reservoir. In the absence of extracellular Ca, Dex suppressed the adrenaline- and histamine-induced increases in contraction tension but did not affect caffeine-induced increases.
CONCLUSIONS
Dex-enhanced, high-concentration KCl-induced contraction was mediated by α-receptors. Adrenaline-induced contraction was suppressed by the α-receptor stimulant Dex and α-receptor antagonists yohimbine and rauwolscine, suggesting that the effect of Dex on adrenaline-induced contraction is attributable to its α-receptor-blocking action. Dex inhibited receptor-activated Ca channels and phosphatidylinositol-1,4,5-triphosphate-induced Ca release but not Ca-induced Ca release.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Calcium; Calcium Channels; Dexmedetomidine; Muscle Contraction; Muscle, Smooth, Vascular; Pulmonary Artery; Swine
PubMed: 31510933
DOI: 10.1186/s12871-019-0843-2 -
Experimental Physiology Dec 2021What is the central question of this study? What is the role of β- and α-adrenergic receptors in the control of the coronary circulation during handgrip exercise and...
NEW FINDINGS
What is the central question of this study? What is the role of β- and α-adrenergic receptors in the control of the coronary circulation during handgrip exercise and isolated muscle metaboreflex activation in humans? What is the main finding and its importance? β-Adrenergic receptor, but not α-adrenergic receptor, blockade significantly blunted the increases in coronary blood velocity observed during handgrip. Coronary blood velocity was unchanged from baseline during isolated muscle metaboreflex activation. This highlights the important role of β-adrenergic receptors in the coronary circulation during handgrip in humans, and the more limited involvement of the α-adrenergic receptors.
ABSTRACT
We sought to investigate the role of β- and α-adrenergic receptors in coronary circulation during static handgrip exercise and isolated muscle metaboreflex activation in humans. Seventeen healthy young men underwent two experimental sessions, consisting of 3 min of static handgrip exercise at a target force of 40% maximum voluntary force (not achieved for the full 3 min), and 3 min of metaboreflex activation (post-exercise ischaemia) in two conditions: (1) control and β-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). In both sessions, coronary blood velocity (CBV, echocardiography) was increased during handgrip (Δ8.0 ± 7.4 cm s ) but unchanged with metaboreflex activation (Δ2.5 ± 3.2 cm s ) under control conditions. β-Blockade abolished the increase in CBV during handgrip, while CBV was unchanged from control with α-blockade. Cardiac work, estimated from rate pressure product (RPP; systolic blood pressure multiplied by heart rate), increased during handgrip and metaboreflex in control conditions in both sessions. β-Blockade reduced RPP responses to handgrip and metaboreflex, whereas α-blockade increased RPP, but the responses to handgrip and metaboreflex were unchanged. CBV and RPP were only significantly correlated during handgrip under control (r = 0.71, P < 0.01) and β-blockade (r = 0.54, P = 0.03) conditions, and the slope of this relationship was unaltered with β-blockade. Collectively, these findings indicate that β-adrenergic receptors play the primary role to the increase of coronary circulation during handgrip exercise, but CBV is unchanged with metaboreflex activation, while α-adrenergic receptor stimulation seems to exert no effect in the control of the coronary circulation during handgrip exercise and isolated muscle metaboreflex activation in humans.
Topics: Blood Pressure; Coronary Circulation; Exercise; Hand Strength; Heart Rate; Humans; Male; Muscle, Skeletal; Sympathetic Nervous System
PubMed: 34719804
DOI: 10.1113/EP089954 -
Pharmaceuticals (Basel, Switzerland) May 2021Quinazoline α-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on...
BACKGROUND
Quinazoline α-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats.
METHODS
Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed.
RESULTS
Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307.
CONCLUSION
MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.
PubMed: 34069933
DOI: 10.3390/ph14050477 -
Mechanisms of Ageing and Development Jan 2022Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic...
BACKGROUND
Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP).
AIM
To elucidate the mechanism of the anti-fibrotic effect of DX and determine whether it induces senescence.
METHODS
Primary culture-activated rat HSCs were used. mRNA and protein expression were measured by qPCR and Western blot, respectively. Cell proliferation was assessed by BrdU incorporation and xCelligence analysis. TGF-β was used for maximal HSC activation. Norepinephrine (NE), PMA and m-3M3FBS were used to activate alpha-1 adrenergic signaling.
RESULTS
Expression of Col1α1 was significantly decreased by DX (10 μmol/L) at mRNA (-30 %) and protein level (-50 %) in TGF-β treated aHSCs. DX significantly reduced aHSCs proliferation and increased expression of senescence and SASP markers. PMA and m-3M3FBS reversed the effect of DX on senescence markers.
CONCLUSION
Doxazosin reverses the fibrogenic phenotype of aHSCs and induces the senescence phenotype.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Agonists; Animals; Cell Cycle Checkpoints; Cell Proliferation; Cells, Cultured; Cellular Senescence; Doxazosin; Hepatic Stellate Cells; Liver Cirrhosis; Norepinephrine; Rats; Receptors, Adrenergic, alpha-1; Senescence-Associated Secretory Phenotype; Signal Transduction; Sulfonamides
PubMed: 34958827
DOI: 10.1016/j.mad.2021.111617