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1.
Background
Both selenium and vitamin D were found to reduce thyroid antibody titers in women with Hashimoto’s thyroiditis.Methods
The study enrolled 37 young drug-naïve euthyroid men with autoimmune thyroiditis, who were treated for 6 months with either exogenous vitamin D (group A, n?=?20) or selenomethionine (group B, n?=?17). Serum titers of thyroid peroxidase and thyroglobulin antibodies, serum levels of thyrotropin and free thyroid hormones, serum levels of 25-hydroxyvitamin D, as well Jostel’s thyrotropin, the SPINA-GT and the SPINA-GD indices were determined at the beginning and at the end of the study.Results
At baseline, there were no differences between the study groups. Both vitamin D and selenomethionine reduced antibody titers and increased the SPINA-GT index. Only selenomethionine affected the SPINA-GD index, while only vitamin D increased 25-hydroxyvitamin D levels. Neither selenomethionine nor vitamin D significantly affected thyrotropin and free thyroid hormone levels. The effect of vitamin D on antibody titers correlated with baseline and treatment-induced changes in serum levels of 25-hydroxivitamin D.Conclusions
Both vitamin D and selenomethionine have a beneficial effect on thyroid autoimmunity in drug-naïve men with Hashimoto’s thyroiditis. 相似文献2.
Background
Both exogenous vitamin D and selenium reduce thyroid antibody titers. The aim of the study was to investigate whether the impact of vitamin D on thyroid autoimmunity is affected by selenium intake.Methods
The study included 47 euthyroid women with Hashimoto’s thyroiditis and low vitamin D status, 23 of whom had been treated with selenomethionine (200?μg daily) for at least 12 months before the beginning of the study. During the study, all patients were treated with vitamin D preparations (4000 IU daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, as well as circulating levels of thyrotropin, free thyroid hormones and 25-hydroxyvitamin D were measured before vitamin D supplementation and 6 months later. Moreover, at the beginning and at the end of the study, we calculated Jostel’s thyrotropin index, the SPINA-GT index and the SPINA-GD index.Results
With the exception of the free triiodothyronine/free thyroxine ratio and the SPINA-GD index, there were no differences between the study groups. In both groups, vitamin D increased 25-hydroxyvitamin D levels, reduced thyroid peroxidase and thyroglobulin antibody titers, as well as increased the SPINA-GT index. The effects on antibody titers and the SPINA-GT index were more pronounced in women receiving selenomethionine. Neither in selenomethionine-treated nor in selenomethionine-naïve women vitamin D affected serum hormone levels, Jostel’s index and the SPINA-GD index.Conclusions
The results of the study suggest that selenium intake enhances the effect of vitamin D on thyroid autoimmunity. 相似文献3.
Insights into the structure and tubulin-targeted anticancer potential of N-(3-bromobenzyl) noscapine
Sanith Cheriyamundath Tejashree Mahaddalkar Praveen Kumar Reddy Nagireddy Balasubramanian Sridhar Srinivas Kantevari Manu Lopus 《Pharmacological reports : PR》2019,71(1):48-53
Background
Noscapine is a non-narcotic, antitussive alkaloid isolated from plants of Papaveraceae family. This benzylisoquinoline alkaloid and its synthetic derivatives, called noscapinoids, are being evaluated for their anticancer potential.Methods
The structure of a novel analogue, N-(3-bromobenzyl) noscapine (N-BBN) was elucidated by X-ray crystallography. Effect of N-BBN on cancer cell proliferation and cellular microtubules were studied by sulphorhodamine B assay and immunofluorescence, respectively. Binding interactions of the alkaloid with tubulin was studied using spectrofluorimetry.Results
N-BBN, synthesized by introducing modification at site B (‘N’ in isoquinoline unit) and a bromo group at the 9th position of the parent compound noscapine, was found to be superior to many of the past-generation noscapinoids in inhibiting cancer cell viability and it showed a strong inhibition of the clonogenic potential of an aggressively metastatic breast tumour cell line, MDA-MB-231. The compound perturbed the tertiary structure of purified tubulin as indicated by an anilinonaphthalene sulfonic acid-binding assay. However, substantiating the common feature of noscapinoids, it did not alter microtubule polymer mass considerably. In cells, the drug-treatment showed a peculiar type of disruption of normal microtubule architecture.Conclusion
N-BBN may be considered for further investigations as a potent antiproliferative agent. 相似文献4.
Jan Detka Joanna Ślusarczyk Anna Kurek Mateusz Kucharczyk Tomasz Adamus Paweł Konieczny Marta Kubera Agnieszka Basta-Kaim Władysław Lasoń Bogusława Budziszewska 《Pharmacological reports : PR》2019,71(2):338-346
Background
In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex – brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions.Methods
Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12?hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase.Results
PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model.Conclusion
Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity. 相似文献5.
Justyna Walenciak Krystyna Wyka Szymon Janczar Wojciech Młynarski Beata Zalewska-Szewczyk 《Pharmacological reports : PR》2019,71(2):311-318
Background
L-asparaginase (L-asp) remains one of the key components of acute lymphoblastic leukemia therapy. Immune reactions to the drug are associated with its diminished activity. The aim of the study was to determine the level of IgM, IgG and IgE-class anti-L-asp antibodies during the induction and reinduction phases of acute lymphoblastic leukemia therapy and their influence on L-asp activity.Methods
The study group comprised 65 patients treated for acute lymphoblastic leukemia in one pediatric oncology center. L-asp antibodies were assessed using ELISA at the end of the induction and reinduction phases. L-asp activity was assessed prior to each drug administration by colorimetry.Results
At the end of the first exposure to L-asp antibodies were detected in 35 patients (54%). In the reinduction phase of the treatment anti-L-asp antibodies were found in 38/55 patients (69%). In the induction phase patients with inadequate L-asp activity had higher IgM concentrations (median 5.88 versus 2.81?μg/mL, p?=?0.03). In the reinduction phase IgG and IgM levels correlated inversely with L-asp activity. Patients with L-asp allergy had higher levels of IgG (median 61.6 versus 18.36 μg/mL, p?=?0.01), whereas higher IgE levels were noted in the group of patients with inadequate drug activity (median 0.91 versus 0.64 μg/mL, p?=?0.03).Conclusions
Subsequent exposure to L-asp in the treatment of acute lymphoblastic leukemia was associated with the increase of anti-L-asp antibodies in all studied classes. However, the changes observed in specific classes of antibodies were not distinctive for L-asp hypersensitivity or inactivation, suggesting that the mechanism is more complex. 相似文献6.
Background
The G protein-coupled receptor 35 (GPR35), is considered important for nociceptive transmission, as suggested by accumulating evidence. This receptor was discovered in 1998; however, a lack of pharmacological tools prevented a complete understanding of its function and how to exploit it therapeutically. We studied the influence of CXCL17, kynurenic acid and zaprinast on nociceptive transmission in naïve and neuropathic mice. Additionally, we investigated the influence of kynurenic acid and zaprinast on morphine effectiveness in neuropathic pain.Methods
The chronic constriction injury (CCI) of the sciatic nerve in Swiss mice was performed. The CXCL17, kynurenic acid, zaprinast and morphine were injected intrathecally into naive and CCI-exposed mice at day 14. To evaluate tactile and thermal hypersensitivity, the von Frey and cold plate tests were used, respectively.Results
Our results have shown, for the first time, that administration of CXCL17 in naïve mice induced strong pain-related behaviours, as measured by von Frey and cold plate tests. Moreover, we demonstrated that kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviours in both tests. Kynurenic acid and zaprinast reduced thermal and tactile hypersensitivity developed by sciatic nerve injury and strongly enhanced the effectiveness of morphine in neuropathy.Conclusions
Our study highlights the importance of GPR35 as a receptor involved in neuropathic pain development. Therefore, these results suggest that the modulation of GPR35 could become a potential strategy for the treatment of neuropathic pain. 相似文献7.
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8.
Jagoda Abramek Jacek Bogucki Marta Ziaja-Sołtys Andrzej Stępniewski Anna Bogucka-Kocka 《Pharmacological reports : PR》2019,71(2):248-256
Background
Sodium dichloroacetate (DCA) is an agent with anticancer properties against solid tumors. DCA also seems to have antileukemic activity. In order to affirm it we investigate the effect of DCA on cell viability and apoptotic gene expression profiles in leukemia cell lines: CEM/C1, CCRF/CEM, HL-60, HL-60/MX2.Methods
Cell viability was assessed by trypan blue staining. The expression of 93 genes involved in the process of apoptosis was determined by real-time PCR method using Taqman Low Density Array (TLDA).Results
CEM/C1, CCRF/CEM, HL-60, HL-60/MX2 cells were exposed to DCA for 24?h. The sensitivity of each cell line to DCA is different and depends on the concentration. CEM/C1 was the most sensitive with an half-maximal inhibitory concentration (IC50) value of 30?mM, while HL-60/MX2 was the most resistant with an IC50 value of 75?mM. Exposure of leukemia cells to DCA causes differences in gene expression profiles which cannot indicate that any particular pathway of apoptosis is initiated. However, the presence of 388 statistically significant correlations between expression pattern of gens was determined.Conclusion
We showed that DCA causes a decrease in viability of leukemia cells. The decline depends on DCA concentration. The induction of any particular apoptosis pathway is not shown in cells after DCA treatment. For that reason, studies on the molecular mechanism of cell death after exposure to DCA should be continued. 相似文献9.
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10.
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11.
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12.
Background
PGs are involved in cellular communication and cancer biology. The role of CS in melanoma and fibrosarcoma cell lines was explored by using chondroitin AC lyase (PsPL8A).Methods
The proliferation of mouse fibroblast L929, human melanoma (SK-Mel 28) and fibrosarcoma (HT-1080) cell lines after treatment with chondroitin AC lyase (PsPL8A) was studied by MTT assay. The mode of cell death was studied by Annexin-V FITC using flow cytometry and fluorescence microscopy. The alteration in mitochondrial cell potential was studied by JC-1 dye using fluorescence microscopy and flow cytometry.Results
Treatment of L929 cells with PsPL8A imparts no cytotoxicity and showed no alteration in proliferation with nearly 95–98% cell viability. An overall 58% and 59% inhibition of SK-Mel 28 and HT-1080 cell proliferation was observed with 1.3 μM of PsPL8A after 24?h of incubation. The PsPL8A (1.3 μM) treated SK-Mel 28 and HT-1080 cells showed significant green fluorescence with annexin-V FITC under fluorescence microscopy and 56.6% and 35.5% apoptosis, respectively by flow cytometry analysis. The results of fluorescence microscopy and flow cytometry of SK-Mel 28 and HT-1080 upon treatment with PsPL8A (1.3 μM) for 24?h, gave green fluorescence due to dissipation of mitochondrial potential with JC-1 dye.Conclusions
Chondroitin AC lyase (PsPL8A) displayed anti-tumor potential against human melanoma SK-Mel 28 and fibrosarcoma HT-1080 cell lines, while the mouse fibroblast L929 cells were unaffected. 相似文献13.
Jarogniew J. Łuszczki Paweł Marzeda Agata Gut-Lepiech Maria W. Kondrat-Wróbel Paula Wróblewska-Łuczka Sławomir Karwan Tomasz Plech 《Pharmacological reports : PR》2019,71(2):299-305
Background
To assess the effects of 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP427) on the protective anticonvulsant action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the tonic-clonic seizure model in mice, an isobolographic transformation of data was used.Methods
Electrically-induced tonic-clonic seizures were experimentally evoked in adult male albino Swiss mice. The anticonvulsant effects of TP427, when used singly, were determined by the calculation of the threshold increasing the dose by 20% (TID20 value). The influence of TP427 on the anticonvulsant potency of four various classical antiepileptic drugs was determined with a subthreshold method. Types of interactions between drugs were determined using the isobolographic transformation of data. Additionally, total brain antiepileptic drug concentrations were measured.Results
TP427, when administered separately, significantly increased the threshold for electroconvulsions. The experimentally determined TID20 value for TP427 was 11.71?mg/kg. Moreover, TP427 (10?mg/kg) significantly increased the anticonvulsant activity of valproate (p?<? 0.01), but not that of carbamazepine, phenobarbital or phenytoin in the mouse tonic-clonic seizure model. Isobolographic transformation of data confirmed that the interaction between TP427 and valproate was synergistic. Pharmacokinetic study revealed that TP427 increased total brain valproate concentrations, and had no impact on total brain concentrations of carbamazepine, phenobarbital or phenytoin in mice.Conclusion
The synergistic interaction between TP427 and valproate in the mouse tonic-clonic seizure model might occur favorable for epilepsy patients in future. The combinations of TP427 with carbamazepine, phenobarbital and phenytoin were additive in the mouse tonic-clonic seizure model and also deserves clinical attention. 相似文献14.
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15.
Background
Due to anti-inflammatory and anti-thrombotic functions, statins and antiplatelets are widely used for patients with cardiovascular-related or coronary artery diseases. Patients with systemic or complex diseases are commonly prescribed multiple targeted medications; thus, a proper combination of two or more drugs for beneficial efficacy is considered in clinical therapy. Recent studies have suggested that combinational therapy with statins and other medications accelerates their single effect to suppress inflammatory responses. However, the therapeutic efficacy and underlying mechanism of combination treatment with rosuvastatin and cilostazol have been poorly studied.Methods
Mice were administered rosuvastatin alone, cilostazol alone or rosuvastatin and cilostazol in combination, and then injected with LPS or TNF to induce acute inflammation. The serum TNF level, macrophage infiltration of the lesioned aortas and mice mortality were observed in the acute inflammation model. The phosphorylation of MAPK was analyzed in TNF-stimulated HeLa cells.Results
Compared to the treatment with cilostazol alone, the combination treatment with rosuvastatin and cilostazol significantly reduced not only the levels of TNF in the sera but also macrophage infiltration in aortic lesions. In addition, the combination therapy decreased TNF-mediated phosphorylation of the MAPK signaling pathway and improved the survival rate in the TNF-driven inflammatory mice model.Conclusion
Rosuvastatin combined with cilostazol therapy can greatly improve the anti-inflammatory effect of monotherapies, resulting in reduced mortality of mice; thus, we propose the potential of use of this combination therapy as anti-TNF agent. 相似文献16.
Iwona Majcher-Maślanka Anna Solarz Agnieszka Chocyk 《Pharmacological reports : PR》2019,71(2):347-350
Background
Corticosteroid-binding globulin (CBG), albumin and 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes play crucial roles in the bioavailability of glucocorticoids. Downstream of the adrenal glands, these proteins affect glucocorticoid levels in target tissues. Early-life stress (ELS) is known to program glucocorticoid action at many levels. The effects of ELS on the concentrations and synthesis of CBG and albumin and on the expression of 11β-HSD remain unclear.Methods
The maternal separation (MS) procedure in rats on postnatal days 1–14 was used as a model of ELS. On postnatal day 35 (adolescence), the serum corticosterone, CBG and albumin concentrations of male rats were measured by ELISA, while the mRNA and protein levels of CBG, albumin and 11β-HSD1 in the liver and brain were examined by RT-qPCR and Western blot, respectively.Results
Under basal conditions, MS rats displayed lower levels of serum CBG and albumin. However, MS did not affect CBG or albumin synthesis in the liver, suggesting that the half-life and/or secretion of these proteins were influenced by MS. Additionally, MS rats showed increased protein expression of 11β-HSD1, specifically in the medial prefrontal cortex.Conclusions
These results indicate that ELS may potentially program glucocorticoid action through its effects on glucocorticoid bioavailability in tissues. 相似文献17.
Beata Wilenska Dagmara Tymecka Marcin Włodarczyk Aleksandra Sobolewska-Włodarczyk Maria Wiśniewska-Jarosińska Jolanta Dyniewicz Árpád Somogyi Jakub Fichna Aleksandra Misicka 《Pharmacological reports : PR》2019,71(1):42-47
Background
Inflammatory bowel diseases (IBD) are a group of chronic and recurrent gastrointestinal disorders that are difficult to control. Recently, a new IBD therapy based on the targeting of the endogenous opioid system has been proposed. Consequently, due to the fact that endogenous enkephalins have an anti-inflammatory effect, we aimed at investigating the degradation of serum enkephalin (Met- and Leu-enkephalin) in patients with IBD.Methods
Enkephalin degradation in serum of patients with IBD was characterized using mass spectrometry methods. Calculated half-life (T1/2) of enkephalins were compared and correlated with the disease type and gender of the patients. Additionally, statistical analysis was used to examine the dynamics of changes in terms of inhibition of enkephalins degradation within research groups.Results
Our research indicates that the degree of enkephalins degradation depends on the gender of the patients. The difference is most evident for the rate of Met-enkephalin degradation between men (mean T1/2?=?13.61?min) and women (mean T1/2 ?=?21.84?min) with Crohn’s disease (CD).Conclusions
The most significant alternation of enkephalins degradation in serum samples of IBD patients, compared to control group, were observed in both Crohn’s disease and ulcerative colitis (UC) female patients. We suggest that the differences observed between the genders in IBD patients may be explained by regulation of enkephalinases activity by estradiol. 相似文献18.
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19.
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20.
Ewelina Kazimierczyk Andrzej Eljaszewicz Paula Zembko Ewa Tarasiuk Malgorzata Rusak Agnieszka Kulczynska-Przybik Marta Lukaszewicz-Zajac Karol Kaminski Barbara Mroczko Maciej Szmitkowski Milena Dabrowska Bozena Sobkowicz Marcin Moniuszko Agnieszka Tycinska 《Pharmacological reports : PR》2019,71(1):73-81