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1.
Lutiana R. Simões Soraia Netto Jaqueline S. Generoso Renan A. Ceretta Rodrigo F. Valim Diogo Dominguini Monique Michels Gislaine Z. Réus Samira S. Valvassori Felipe Dal-Pizzol Tatiana Barichello 《Pharmacological reports : PR》2019,71(1):24-31
Background
A periodontal lesion is a consequence of chronic inflammatory processes, itself triggered by a bacterial infection of the pulpal and endodontic microenvironment. Evidence suggests that periodontal lesion induction could alter inflammatory cytokines leading to behavior changes. These effects in the context of anxiety and depressive behavior have been not full investigated. We aimed to observe anxiety- and depressive-like behavioral in rodent subjected to periapical dental lesions.Methods
Pro-inflammatory cytokines levels also were investigated in the frontal cortex and hippocampus. Parameters related to hypothalamic–pituitary–adrenal (HPA) axis activation also were evaluated. Wistar rats were divided in groups: control/saline; control/imipramine; periapical lesion/saline; and periapical lesion/imipramine. Three weeks after induction of the periapical dental lesion, they were subjected to behavioral tests.Results
In the periapical lesion group was demonstrated anhedonic behavior and depressive-like behavior. In the elevated plus-maze test the periapical lesion group had an increase in the number of entries and spent more time in the closed arms. Imipramine treatment was able to reverse depressive- and anxiety-like behaviors. In the hippocampus and frontal cortex tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and serum adrenocorticotropic hormone (ACTH) levels were higher in the periapical lesion group. However, rats treated with imipramine had lower IL-1β and ACTH levels.Conclusions
Our results revealed depressive- and anxiety-like behaviors following induction of a specific dental lesion. These effects could be associated to higher levels of brain pro-inflammatory cytokines and HPA axis changes. Antidepressants treatments could be an alternative to treat comorbidities associated to periodontal lesions. 相似文献2.
Wojciech Garczorz Enrique Gallego-Colon Agnieszka Kosowska Krzysztof Siemianowicz Agnieszka Kłych-Ratuszny Michał Woźniak Mohammad Reza F. Aghdam Tomasz Francuz Mariola Dorecka 《Pharmacological reports : PR》2019,71(1):175-182
Background
Diabetic retinopathy (DR) is one of the most common complications of diabetes and the leading cause of acquired blindness in adults. In diabetic patients hyperglycemia induces complex metabolic abnormalities affecting retinal homeostasis, and promotes retinal inflammation and angiogenesis. Incretin mimetic drugs such exenatide, are a relatively new group of drugs used in the treatment of diabetes. We investigated the potential direct effects of exenatide on human retinal pigment epithelium (HRPE).Methods
cAMP production was measured after stimulation of HRPE cells with GLP-1 and exenatide. Intracellular signaling pathways were also examined. HRPE cells were stimulated with TNF-α and subsequently incubated with exenatide. The concentration of metalloproteinases, MMP-1, MMP-2 and MMP-9, and tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and TIMP-3 were evaluated. Viability, cytotoxicity and caspase 3/7 activation were determined. Activity of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in GLP-1 inactivation, was also determined.Results
Both GLP-1 and exenatide stimulation in HRPE cells caused no effect in cAMP levels suggesting alternative signaling pathways. Signaling pathway analysis showed that exenatide reduced phosphorylation of Akt-Ser473, PRAS40, SAPK/JNK, Bad, and S6 proteins but not Akt-Thr308. Exenatide also decreased MMP-1, MMP-9, and TIMP-2 protein levels whereas MMP-2 level in HRPE cells was increased. Finally, we show that exenatide decreased the activity of DPP-4 in TNF-α stimulated HRPE cells.Conclusions
These findings indicate that exenatide modulates regulation of extracellular matrix components involved in retinal remodeling. 相似文献3.
Mohammed I. Rasool Ahsan F. Bairam Saud A. Gohal Amal A. El Daibani Fatemah A. Alherz Maryam S. Abunnaja Eid S. Alatwi Katsuhisa Kurogi Ming-Cheh Liu 《Pharmacological reports : PR》2019,71(2):257-265
Background
Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes.Methods
Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure.Results
Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP.Conclusion
Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes. 相似文献4.
Narges Habibian Mahsa M. Amoli Farzaneh Abbasi Ali Rabbani Abbas Alipour Fatemeh Sayarifard Parastoo Rostami Somayeh Parichehreh Dizaji Babak Saadati Aria Setoodeh 《Pharmacological reports : PR》2019,71(2):282-288
Background
After the onset of type 1 diabetes mellitus (T1DM), preservation of the residual ß-cell function can help good metabolic control. The aim of this study was to evaluate the effect of vitamin D and its receptor gene polymorphisms on residual ß-cells function.Methods
One hundred and one children with T1DM (new cases) older than 5 years were selected. Vitamin D receptor (VDR) gene polymorphisms, vitamin D (VD), fasting and stimulated C-peptide (FCP and SCP) levels were measured within 1.5 and 4.5 month after the diagnosis of disease. Kruskal-Wallis and Mann-whitney U test were used for comparing the study groups. Generalized estimating equation (GEE) model was used for the estimation of association between VD and VDR gene polymorphisms with FCP and SCP after adjustment for comorbid variables.Results
The most frequent genotypes and alleles in TaqI, FokI, BsmI and ApaI polymorphisms were TT (50%) and allele T (68.88%), FF (59.2%) and allele F (77.04%), Bb (41.8%) and allele b (61.73%), and Aa (53.1%) and allele A (63.29%) respectively. In children with higher VD levels, the C-peptide (CP) levels were elevated. Also we observed: the tt genotype associated with increasing SCP levels compared with TT genotype; the bb and Bb genotypes were associated with increasing both FCP and SCP in comparison to BB; and the aa and Aa genotypes were associated with decreasing FCP in comparison to the AA genotype.Conclusions
Sufficient levels of VD (more than 30?ng/ml) can preserve residual ß-cells and insulin secretion. 相似文献5.
Background
Transient receptor potential ankyrin-1 (TRPA1) channels expressed in the central terminal of dorsal root ganglion neurons in the spinal substantia gelatinosa (SG) play a role in modulating nociceptive transmission. Although plant-derived compounds exhibiting antinociception (such as eugenol, carvacrol and thymol) activate TRPA1 channels to enhance spontaneous excitatory transmission while hyperpolarizing membranes in SG neurons without TRPA1 activation, specific chemical moieties involved in synaptic modulation are unknown.Methods
We examined the effects of other plant-derived compounds (guaiacol, vanillin, vanillic acid and p-cymene) on holding current and spontaneous excitatory transmission at ?70?mV by applying the whole-cell patch-clamp technique to SG neurons in adult rat spinal cord slices.Results
None of the compounds affected the frequency or amplitude of spontaneous excitatory postsynaptic current. Guaiacol and vanillic acid had no effect on holding currents, while vanillin and p-cymene produced an inward and outward current, respectively, in some neurons tested. Synaptic modulation was also observed within the same neuron as the activities of eugenol, carvacrol, thymol, and the chemically-related plant-derived compound zingerone occurred.Conclusion
A substituted group in eugenol and zingerone, but not in guaiacol, vanillin or vanillic acid, as well as an OH bound to the benzene ring of carvacrol and thymol, but not p-cymene, play a role in producing outward current and TRPA1 activation. Thus, the binding of such chemical moeties to the benzene ring of plant-derived compounds appears necessary to modulate nociceptive transmission in the SG. This information provides insight for the development of new analgesics based on plant-derived compounds. 相似文献6.
Refaat I. ElFayoumi Magda M. Hagras Adel Abozenadaha Mamdouh Gari Ibrahim Abosoudah Thoraia Shinawi Talaat Mirza Waleed Bawazir 《Pharmacological reports : PR》2019,71(1):90-95
Background
Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL.Methods
Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC).Results
Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p?=?0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034–8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486–19.198).Conclusions
In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage. 相似文献7.
Reza Fartootzadeh Fatemeh Azizi Hojjatallah Alaei Parham Reisi 《Pharmacological reports : PR》2019,71(2):361-366
Background
The nucleus accumbens core (NAcc) expresses both orexin and nicotinic acetylcholine receptors (nAChRs). Orexin is among important neurotransmitters, which regulates addictive properties of drugs of abuse including nicotine. The role of orexin-2 receptor (OX2R) in the regulation of NAcc neural activity in response to nicotine has not yet been studied. Hence, in this study, we examined whether the OX2R antagonist (TCS-OX2-29) can adjust the effects of nicotine on electrical activity of NAcc neurons, in urethane-anesthetized rats, using the single unit recording.Methods
Neuronal firing of NAcc was recorded for 15?min, then TCS-OX2-29 (OX2R-antagonist; 1, 3 and 10?ng/rat) or DMSO were microinjected into NAcc, just 5?min before subcutaneous (sc) administration of nicotine (0.5?mg/kg) or saline. The spontaneous firing activity was recorded for 70?min, after nicotine injection.Results
The results demonstrated that nicotine significantly excites the NAcc neurons and interestingly, the administration of TCS-OX2-29 (3 and 10?ng/rat) into the NAcc, inhibited nicotine-induced increases of NAcc neuronal responses. Furthermore, administration of TCS-OX2-29 (10?ng/rat), just 5?min before sc administration of saline instead of nicotine, did not significantly alter the neuronal responses, compared to the saline-control group.Conclusion
Our results showed that, although OX2R blockade alone did not affect neuronal activity in the NAcc, it was able to prevent the exciting effects of nicotine on NAcc neuronal activity. Therefore, we proposed that orexin has a potential modulator effect, in response to nicotine. 相似文献8.
Background
The osmolyte and antioxidant taurine plays an important role in regulation of cellular volume, oxidative status and Ca2+-homeostasis. Taurine uptake in human cells is regulated by the Na+- and Cl?-dependent taurine transporter TauT. In order to gain deeper structural insights about the substrate binding pocket of TauT, a HEK293 cell line producing a GFP-TauT fusion protein was generated.Methods
Transport activity was validated using cell-based [3H]-taurine transport assays. We determined the Km and IC50 values of taurine, β-alanine and γ-aminobutyrate. Additionally we were able to identify structurally similar compounds as potential new substrates or inhibitors of the TauT transporter. Substrate induced cytotoxicity was analyzed using a cell viability assay.Results
In this study we show competitive effects of the 3-pyridinesulfonate, 2-aminoethylhydrogen sulfate, 5-aminovalerate, β-aminobutyrate, piperidine-4-sulfonate, 2-aminoethylphosphate and homotaurine. We demonstrate that taurine uptake can be inhibited by a phosphate. Furthermore our studies revealed that piperidine-4-sulfonate interacts with TauT with a higher affinity than γ-aminobutyrate and imidazole-4-acetate.Conclusion
We propose that piperidine-4-sulfonate may serve as a potential lead structure for the design of novel drug candidates required for specific modulation of the TauT transporter in therapy of neurodegenerative diseases. 相似文献9.
Zuyue Chen Hong Wei Boriss Sagalajev Ari Koivisto Antti Pertovaara 《Pharmacological reports : PR》2019,71(1):54-60
Background
The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior.Methods
Rats with a spared nerve injury (SNI) model of neuropathy or sham operation had a chronic cannula for drug microinjections into the CeA or a control injection site. Monofilament test was used to evaluate pain, and light-dark box (LDB) to assess anxiety.Results
Perioperative CeA treatment with TPA (30?μg/day up to the third postoperative day, D3) significantly attenuated the development of pain and anxiety-like behavior. In the late phase (> D14), CeA administration of TPA (3–30?μg) failed to influence pain. Perioperative minocycline (microglia inhibitor; 25?μg), MK-801 (an N-Methyl-D-aspartate receptor antagonist; 0.1?μg), vehicle or TPA in a control injection site failed to attenuate pain development.Conclusions
Perioperative treatment of the CeA with TPA delayed development of neuropathic pain and comorbid anxiety-like behavior, while TPA treatment failed to influence maintenance of established neuropathic pain. The failures to attenuate pain development with CeA administrations of minocycline or MK-801 do not support the hypothesis that the TPA-induced prophylactic effect was due to inhibition of amygdaloid microglia or N-methyl-D-aspartate receptors. While TPA in the CeA proved to have a prophylactic effect on SNI-induced pain behavior, the underlying mechanism still remains to be studied. 相似文献10.
Yosuke Suzuki Nanako Muraya Takashi Fujioka Fuminori Sato Ryota Tanaka Kunihiro Matsumoto Yuhki Sato Keiko Ohno Hiromitsu Mimata Satoshi Kishino Hiroki Itoh 《Pharmacological reports : PR》2019,71(2):276-281
Background
Phenoconversion is a phenomenon whereby some genotypic extensive metabolizers transiently exhibit drug metabolizing enzyme activity at similar level as that of poor metabolizers. Renal failure is known to decrease CYP3A activity in humans. Indoxyl sulfate, parathyroid hormone (PTH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been reported to cause CYP3A downregulation in renal failure. We measured plasma concentrations of the above compounds in stable kidney transplant recipients, and evaluated their relations with phenoconversion of CYP3A evaluated by plasma concentration of 4β-hydroxycholesterol, a biomarker of CYP3A activity. Phenoconversion was defined as a genotypic extensive/intermediate metabolizer exhibiting CYP3A activity below the cutoff value that discriminates extensive/intermediate from poor metabolizers.Methods
Sixty-three Japanese kidney transplant recipients who underwent transplantation more than 180 days prior to the study were included. Morning blood samples were collected, and CYP3A5 polymorphism as well as plasma concentrations of 4β-hydroxycholesterol, indoxyl sulfate, intact-PTH, IL-6 and TNF-α were determined.Results
Significantly higher plasma 4β-hydroxycholesterol concentration was observed in recipients with CYP3A5*1 allele (n?=?23) compared to those without the allele (n?=?40), and the cut-off value was 40.0?ng/mL. Ten recipients with CYP3A5*1 allele exhibited CYP3A activity below 40.0?ng/mL (phenoconversion). Only plasma indoxyl sulfate concentration was significantly higher in recipients with CYP3A phenoconversion compared to those without phenoconversion.Conclusions
These findings suggest that higher plasma indoxyl sulfate concentration may be involved in CYP3A phenoconversion. Dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high blood indoxyl sulfate. 相似文献11.
Marek Zadrozniak Marcin Szymanski Jarogniew J. Luszczki 《Pharmacological reports : PR》2019,71(2):351-356
Background
Drug-induced ototoxicity is still a main clinical problem in otolaryngology. It is widely known that aminoglycoside antibiotics combined with loop diuretics significantly contribute to permanent ototoxicity. The aim of this study was to find out whether ascorbic acid (vitamin C) is able to reverse or alleviate ototoxicity evoked by systemic (ip) administration of combination of amikacin and furosemide in experimental male albino Swiss mice.Methods
Ototoxic combination of amikacin and furosemide was isobolographically evaluated based on the hearing threshold decreasing doses by 20% and 50% (TDD20 and TDD50), respectively. Linear regression analysis was used to determine the TDD20 and TDD50 values for amikacin, furosemide, vitamin C administered alone and in combination (at the fixed-ratio of 1:1).Results
Vitamin C (in a dose of 500?mg/kg, ip) alleviated the impairment in hearing threshold evoked by combined ip administration of amikacin and furosemide (at the fixed-ratio of 1:1) in mice by reducing TDD50 values from 49.82 to 21.56 (p?<? 0.01). In contrast, vitamin C (500?mg/kg, ip) had no significant effect on TDD20 values for the combination of amikacin and furosemide at the fixed-ratio of 1:1.Conclusions
Vitamin C administered together with ototoxic drug combination of amikacin and furosemide reduced ototoxicity evoked by this two-drug combination in the experimental mice. 相似文献12.
Ewa Langner Witold Jeleniewicz Waldemar A. Turski Tomasz Plech 《Pharmacological reports : PR》2019,71(2):189-193
Background
Origin, synthesis and activity of quinaldic acid (QA), proposed derivative of kynurenic acid, have been poorly studied to date. Previously, we have demonstrated the antiproliferative effect of QA in a colon cancer model in vitro. The goal of present study was to verify QA activity to modify the expression of p53 tumor suppressor in colon cancer cells, and to relate it to its cancer cell growth inhibiting activity in vitro.Methods
LS180 colon cancer cells possessing the wild type form of p53 were used in the study. Real-time PCR and immunobloting techniques were used to test the expression of p53 at gene and protein level, respectively. Next, immunocytochemistry was used to visualize the localization of p53 protein within the cells. Furthermore, the antiproliferative activity of QA was retested in cells with siRNA silenced P53 gene.Results
The activity of QA to modify both the expression and phosphorylation of p53 protein as well as the level of P53 gene is shown. Concomitantly, the nuclear and cytoplasmic localization of phospho-p53 protein upon QA treatment is also presented. Moreover, reduced activity of QA in colon cancer cells with silenced p53 expression is observed.Conclusion
QA affects the expression of p53 tumor suppressor, both at gene and protein level. The prominent contribution of p53 to the antiproliferative effect of QA in LS180 colon cancer cells can be suggested. 相似文献13.
Parham Jabbarzadeh Kaboli Melody Pui-Yee Leong Patimah Ismail King-Hwa Ling 《Pharmacological reports : PR》2019,71(1):13-23
Background
Berberine is an alkaloid plant-based DNA intercalator that affects gene regulation, particularly expression of oncogenic and tumor suppressor proteins. The effects of berberine on different signaling proteins remains to be elucidated. The present study aimed to identify the effects of berberine against key oncogenic proteins in breast cancer cells.Methods
Molecular docking and molecular dynamics simulations were used for EGFR, p38, ERK1/2, and AKT. The effects of berberine and lapatinib on MAPK and PI3K pathways in MDA-MB231 and MCF-7 cells were evaluated using immunoflorescence assays, and the amounts of phosphorylated kinases were compared to total kinases after treating with different concentrations of berberine.Results
Simulations showed berberine accurately interacted with EGFR, AKT, P38, and ERK1/2 active sites in silico (scores = -7.57 to -7.92 Kcal/mol) and decreased the levels of active forms of corresponding enzymes in both cell lines; however, berberine binding to p38 showed less stability. Cytotoxicity analysis indicated that MDA-MB231 cells were resistant to berberine compared to MCF-7 cells [72?h IC50?=?50 versus 15 μM, respectively). Also, lapatinib strongly activated AKT but suppressed EGFR in MDA-MB231 cells. The activity of EGFR, AKT, P38, and ERK1/2 were affected by berberine; however, berberine dramatically reduced EGFR and AKT phosphorylation.Conclusion
By way of its multikinase inhibitory effects, berberine might be a useful replacement for lapatinib, an EGFR inhibitor which can cause acquired drug resistance in patients. 相似文献14.
Gabriela Handzlik Michał Holecki Joanna Kozaczka Michał Kukla Katarzyna Wyskida Leszek Kędzierski Krzysztof Pawlicki Jan Duława 《Pharmacological reports : PR》2019,71(2):183-188
Background
Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disease worldwide. There is growing evidence on pathogenesis and pathophysiology of NAFLD. However, there is still no universally accepted pharmacotherapy protocol.Methods
The study was conducted on 42 patients with NAFLD. They were randomized to dietary treatment alone (n?=?21) or to diet and metformin therapy (n?=?21). Liver ultrasonography, controlled attenuation parameter (CAP), liver stiffness (LS), complete blood count, anthropometric and biochemical parameters were obtained before treatment (baseline), and after 3 and 5 months of the therapy.Results
Patients treated with diet and metformin exhibited significantly decreased CAP values at 3 and 5 months of the therapy compared to baseline (319?dB/m vs. 285?dB/m; p < 0.05; 319?dB/m vs. 295?dB/m; p < 0.05 respectively). Five months of diet and the metformin therapy resulted in significant reduction of LS value (6.2?kPa vs. 5.2?kPa; p?<? 0.05), while patients treated with diet alone had no significant changes in liver CAP and LS measurements.Conclusions
Metformin therapy combined with dietary treatment seems to be effective for the reduction of hepatic steatosis and fibrosis. However, considering limitations of the study and inconsistent results of previous investigations in this area, there is a need for further research on metformin efficacy in this group of patients. 相似文献15.
Duygun Altıntaş Aykan Tuba Tulay Koca Selma Yaman Nadire Eser 《Pharmacological reports : PR》2019,71(2):306-310
Background
We hypothesized that renin-angiotensin system and neprilysin (NEP) inhibition can modulate the nociceptive parameters on hypertensive rats. The aim of this study is to assess the preventive and therapeutic effects of ramipril and sacubitril on the pain hypersensitivities, and their interaction mechanisms with high blood pressure.Methods
Antinociceptive effects of ramipril and sacubitril were compared with those of diclofenac. Threshold of pain assesments were recorded before drugs administration. After a 18 days treatment, normotensive and dexamethasone-induced hypertensive rats were evaluated on thermal hyperalgesia and mechanical allodynia tests. Blood pressure of rats were verified by mean arterial pressure measurement.Results
Hypertensive rats showed significantly high pain threshold on thermal plantar test compared to that of normotensives. Among hypertensive rats, pain hypersensitivity was lowest in diclofenac group, followed by sacubitril group, while ramipril caused increased thermal and mechanical hypersensitivities.Conclusion
We found that NEP inhibition may play a role in nociception in hypertensive rats. NEP inhibitors may be suitable choice for the management of hypertension and pain because of their therapeutic and preventive effects on nociception and arterial blood pressure. 相似文献16.
Background
Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α1-adrenoceptors (α1-ARs). Inhibition of such an activity at α1-AR subtypes by antagonists with negative efficacy is difficult to be adequately tested.Methods
In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α1-AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α1A/α1B-α1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α1D-AR, that is the α1- AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist.Results
We found that all the three benzodioxane-related α1-AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers.Conclusions
Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α1-AR antagonist is related neither to a particular profile of α1-AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α1-AR antagonists with L-type Ca2+ channels. 相似文献17.
Background
Elevated prolactin levels are associated with increased cardiometabolic risk. No previous study has compared the effect of hypolipidemic therapy on plasma levels of lipids and other cardiometabolic risk factors in patients with and without hyperprolactinemia.Methods
The study included three age-, weight-, blood pressure- and lipid-matched groups of premenopausal women: 18 women with untreated hyperprolactinemia, 19 women with bromocriptine-treated hyperprolactinemia and 20 drug-naïve women with normal prolactin levels. Because of concomitant atherogenic dyslipidemia, all patients were treated with fenofibrate (200?mg daily) for 12 weeks. Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen were assessed at baseline and at the end of hypolipidemic treatment.Results
Unlike similar baseline lipid levels, plasma concentrations of the remaining investigated cardiometabolic risk factors were higher in women with elevated prolactin levels than in patients with normal prolactin levels. The impact of fenofibrate on total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels, as well as on uric acid, hsCRP, homocysteine, and fibrinogen was less pronounced in women with untreated hyperprolactinemia than in women with bromocriptine-treated hyperprolactinemia and drug-naïve women with normal prolactin levels.Conclusions
The results of our study indicate that cardiometabolic effects of fenofibrate depend on plasma prolactin levels. 相似文献18.
Aleksandra Sałagacka-Kubiak Marta Żebrowska-Nawrocka Agnieszka Jeleń Marek Mirowski Ewa Balcerczak 《Pharmacological reports : PR》2019,71(2):272-275
Background
CYP2C19 isoenzyme of cytochrome P450 in the liver catabolises proton pump inhibitors, one of the therapeutics utilized in Helicobacter pylori eradication therapy, and in this way could influence the eradication effectiveness. The isoensyme contributes also to metabolism of endogenous substances, which derivatives are involved in the pathogenesis of peptic ulceration. CYP2C19*2 polymorphism (rs4244285) changing the CYP2C19 function could be relevant in the predisposition to peptic ulcer disease.Methods
CYP2C19*2 polymorphism in 197 peptic ulcer patients and 107 healthy subjects of Polish origin by PCR-RFLP method was investigated.Results
There were no statistically significant differences in genotypes and alleles frequencies for investigated polymorphism between peptic ulcer patients and healthy individuals. No associations between frequencies of particular CYP2C19 genotypes and alleles and the presence of H. pylori infection in peptic ulcer patients were stated. However, significant association between CYP2C19*2 and gender in H. pylori-infected but not -uninfected peptic ulcer individuals was found.Conclusions
Investigated polymorphism is not a risk factor for peptic ulcer in Polish population. Obtained results could suggested there is some interaction between gender, CYP2C19*2 polymorphism, and pathogenesis of H. pylori infection development. However, this hypothesis should be verified in the further studies. 相似文献19.
Fatemeh Delrobaei Iman Fatemi Ali Shamsizadeh Mohammad Allahtavakoli 《Pharmacological reports : PR》2019,71(1):133-138
Background
Menopause is associated with increased oxidative stress and memory impairment. Based on the antioxidant property of ascorbic acid (AA), It’s effect on cognitive function, the serum level of the brain-derived neurotrophic factor (BDNF) and the activity of antioxidant enzymes within the brain in ovariectomized (OVX) mice was investigated.Methods
AA (100, 300 and 500?mg/kg), was orally administrated per day in OVX mice for 30 days. Tactile learning and working memory were evaluated by the novel object recognition task and T-maze continuous alternation task, respectively. The levels of serum BDNF were measured and animals’ brains were analyzed for the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity.Results
AA prevented from the deleterious effects of ovariectomy on learning memory (300 and 500?mg/kg) and working memory (100 and 500?mg/kg). The serum BDNF level was also increased in OVX animals treated with AA (100 and 500?mg/kg). Furthermore, AA (500?mg/kg) increased the SOD and GPx activity in the brain of OVX animals.Conclusions
Collectively, the results of the present study suggest that AA might be an appropriate choice in loss or reduction of estradiol for the amelioration of cognitive impairment. 相似文献20.
Yueh-Lun Lee Ling-Heng Hsu Yueh-Hsiung Kuo Chen-Chen Lee 《Pharmacological reports : PR》2019,71(2):194-200
