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1.
Int J Mol Sci ; 22(13)2021 Jul 02.
Article in English | MEDLINE | ID: mdl-34281228

ABSTRACT

Prostate (PC) and breast cancer (BC) are heterogeneous hormonal cancers. Treatment resistance and adverse effects are the main limitations of conventional chemotherapy treatment. The use of sensitizing agents could improve the effectiveness of chemotherapeutic drugs as well as obviate these limitations. This study analyzes the effect of single catechin (CAT), procyanidin B2 (ProB2) treatment as well as the co-adjuvant treatment of each of these compounds with docetaxel (DOCE). We used PC- and BC-derived cell lines (PC3, DU-145, T47D, MCF-7 and MDA-MB-231). The short and long-term pro-apoptotic, anti-proliferative and anti-migratory effects were analyzed. RT-qPCR was used to discover molecular bases of the therapeutic efficacy of these compounds. ProB2 treatment induced a two- to five-fold increase in anti-proliferative and pro-apoptotic effects compared to single DOCE treatment, and also had a more sensitizing effect than DOCE on DU145 cells. Regarding BC cells, ProB2- and CAT-mediated sensitization to DOCE anti-proliferative and pro-apoptotic effects was cell-independent and cell-dependent, respectively. Combined treatment led to high-efficacy effects on MCF-7 cells, which were associated to the up-regulation of CDKN1A, BAX, caspase 9 and E-cadherin mRNA under combined treatment compared to single DOCE treatment. CAT and ProB2 can enhance the efficacy of DOCE therapy on PC and BC cells by the sensitizing mechanism.


Subject(s)
Antineoplastic Agents/therapeutic use , Biflavonoids/therapeutic use , Breast Neoplasms/drug therapy , Catechin/therapeutic use , Docetaxel/therapeutic use , Proanthocyanidins/therapeutic use , Prostatic Neoplasms/drug therapy , Drug Screening Assays, Antitumor , Drug Therapy, Combination , Female , Humans , In Vitro Techniques , MCF-7 Cells , Male
2.
J Med Chem ; 64(1): 458-480, 2021 01 14.
Article in English | MEDLINE | ID: mdl-33372800

ABSTRACT

We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure-activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38 Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.


Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A2B/drug effects , Adenosine A2 Receptor Antagonists/metabolism , Animals , CHO Cells , Cricetulus , Cyclic AMP/metabolism , HEK293 Cells , HeLa Cells , Humans , Models, Molecular , Neoplasm Metastasis/prevention & control , Pyrimidines/chemistry , Pyrimidines/metabolism , Radioligand Assay , Receptor, Adenosine A2B/metabolism , Stereoisomerism , Structure-Activity Relationship
3.
Antibiotics (Basel) ; 8(4)2019 Oct 30.
Article in English | MEDLINE | ID: mdl-31671525

ABSTRACT

Antibiotic resistance is an emerging worldwide concern with serious repercussions in terms of morbi-mortality. Bearing in mind that the inadequate use of antibiotics, by healthcare staff as well as by the general population, is one of its main causes, a multidisciplinary approach is required to try to combat it. The aim of the present study was to determine nursing students' knowledge and awareness of antibiotic use, resistance and stewardship. A cross-sectional design was used. A total of 578 nursing students from the University of Santiago de Compostela (Spain), ≥18 years old of both sexes were invited to complete the Spanish version of the questionnaire "Knowledge and awareness of the use, resistance and administration of antibiotics" between February and April 2019. Students had a low level of knowledge about antibiotics, 4.1 (CI95% = 3.4-4.8), especially in relation to antibiotic resistance. As the students were aware of this deficiency, the majority affirmed (>90%) that the current curriculum of nursing degree should have more training on antibiotics and infection control. Nursing staff play an important role in the rational use of antibiotics and as teachers of patients, so their training could be key in fighting antibiotic resistance.

4.
Int J Mol Sci ; 20(20)2019 Oct 09.
Article in English | MEDLINE | ID: mdl-31600887

ABSTRACT

Glucosinolate-degradation products (GS-degradation products) are believed to be responsible for the anticancer effects of cruciferous vegetables. Furthermore, they could improve the efficacy and reduce side-effects of chemotherapy. The aim of the present study was to determine the cytotoxic effects of GS-degradation products on androgen-insensitive human prostate cancer (AIPC) PC-3 and DU 145 cells and investigate their ability to sensitize such cells to chemotherapeutic drug Docetaxel (DOCE). Cells were cultured under growing concentrations of allyl-isothiocyanate (AITC), sulforaphane (SFN), 4-pentenyl-isothiocyanate (4PI), iberin (IB), indole-3-carbinol (I3C), or phenethyl-isothiocyanate (PEITC) in absence or presence of DOCE. The anti-tumor effects of these compounds were analyzed using the trypan blue exclusion, apoptosis, invasion and RT-qPCR assays and confocal microscopy. We observed that AITC, SFN, IB, and/or PEITC induced a dose- and time-dependent cytotoxic effect on PC-3 and DU 145 cells, which was mediated, at least, by apoptosis and cell cycle arrest. Likewise, we showed that these GS-degradation products sensitized both cell lines to DOCE by synergic mechanisms. Taken together, our results indicate that GS-degradation products can be promising compounds as co-adjuvant therapy in prostate cancer.


Subject(s)
Adjuvants, Pharmaceutic , Antineoplastic Agents, Phytogenic/pharmacology , Glucosinolates/pharmacology , Prostatic Neoplasms/etiology , Prostatic Neoplasms/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemoprevention , Dose-Response Relationship, Drug , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology
5.
Molecules ; 21(5)2016 May 12.
Article in English | MEDLINE | ID: mdl-27187332

ABSTRACT

Despite the major progress made in the field of cancer biology, cancer is still one of the leading causes of mortality, and prostate cancer (PCa) is one of the most encountered malignancies among men. The effective management of this disease requires developing better anticancer agents with greater efficacy and fewer side effects. Nature is a large source for the development of chemotherapeutic agents, with more than 50% of current anticancer drugs being of natural origin. Isothiocyanates (ITCs) are degradation products from glucosinolates that are present in members of the family Brassicaceae. Although they are known for a variety of therapeutic effects, including antioxidant, immunostimulatory, anti-inflammatory, antiviral and antibacterial properties, nowadays, cell line and animal studies have additionally indicated the chemopreventive action without causing toxic side effects of ITCs. In this way, they can induce cell cycle arrest, activate apoptosis pathways, increase the sensitivity of resistant PCa to available chemodrugs, modulate epigenetic changes and downregulate activated signaling pathways, resulting in the inhibition of cell proliferation, progression and invasion-metastasis. The present review summarizes the chemopreventive role of ITCs with a particular emphasis on specific molecular targets and epigenetic alterations in in vitro and in vivo cancer animal models.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Brassicaceae/chemistry , Isothiocyanates/therapeutic use , Prostatic Neoplasms/drug therapy , Animals , Anticarcinogenic Agents/chemistry , Anticarcinogenic Agents/isolation & purification , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Disease Models, Animal , Humans , Isothiocyanates/chemistry , Isothiocyanates/isolation & purification , Male
6.
Chembiochem ; 15(10): 1471-80, 2014 Jul 07.
Article in English | MEDLINE | ID: mdl-24943831

ABSTRACT

An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 µM, EC50 =3.63 µM) and 22 (IC50 =1.37 µM, EC50 =6.90 µM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Drug Design , Kinesins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Kinesins/chemistry , Kinesins/metabolism , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity Relationship
7.
Basic Clin Pharmacol Toxicol ; 111(3): 206-10, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22540866

ABSTRACT

During periods of psychological stress, excess amounts of free radicals are produced. Bilirubin oxidative metabolites (biopyrrins; BOM) are generated from bilirubin as a result of its scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrins is altered by anxiolytics. In the present study, mice were immobilized for a period of 6 hr. Alprazolam (0.1-1 mg/kg of body-weight) was administered 30 min. before subjecting the animals to acute stress. The BOM concentrations in urine and the corticosterone levels in serum were measured by ELISA with an anti-bilirubin antibody and EIA, respectively. We observed an increase in urinary biopyrrins in stressed mice in comparison with non-stressed mice and a decrease after the treatment of stressed animals with alprazolam. A correlation between urinary BOM and serum corticosterone levels was found. Urinary levels of biopyrrins might be used to assess the response to anxiolytics prescribed during acute stress periods.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Bilirubin/analogs & derivatives , Biomarkers/urine , Stress, Psychological/drug therapy , Alprazolam/administration & dosage , Alprazolam/toxicity , Animals , Bilirubin/urine , Corticosterone/blood , Depression/chemically induced , Depression/drug therapy , Enzyme-Linked Immunosorbent Assay , Male , Mice , Oxidation-Reduction , Stress, Psychological/pathology , Treatment Outcome
8.
Life Sci ; 89(17-18): 650-4, 2011 Oct 24.
Article in English | MEDLINE | ID: mdl-21851827

ABSTRACT

AIMS: Stress can cause adverse reactions in the body that induce a wide range of biochemical and behavioral changes. Oxidative damage is an established outcome of stress that has been implicated in the pathogenesis of mood and anxiety disorders. Anxiolytic drugs are widely prescribed to treat these conditions; however, no animal study has investigated the effect of benzodiazepines on the levels of intracellular reactive oxygen species (ROS) in the peripheral blood leukocytes of stressed mice. MAIN METHODS: Mice were immobilized for a period of 6h. Alprazolam (0.1-0.8 mg/kg of body weight) was administered 30 min before subjecting the animals to acute stress. The level of intracellular ROS in lymphocytes, granulocytes, and monocytes in the peripheral blood of stressed mice was investigated by using a 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. KEY FINDINGS: Our results show that restraint stress significantly increases the generation of ROS in peripheral defense cells. Treatment with alprazolam partially reverses the adverse effects of stress. SIGNIFICANCE: Our findings suggest that the therapeutic efficacy of alprazolam may be mediated, at least partially, by the reversal of oxidative damage as demonstrated by the protective enhancement of antioxidant status following a stress-induced decline. Because alprazolam is used for the treatment of anxiety in patients with cancer, neurodegenerative disease, inflammatory bowel diseases, and other diseases, these results may have important clinical implications.


Subject(s)
Alprazolam/pharmacology , Anti-Anxiety Agents/pharmacology , Antioxidants/pharmacology , Leukocytes/drug effects , Reactive Oxygen Species/metabolism , Stress, Physiological/drug effects , Animals , Granulocytes/drug effects , Granulocytes/metabolism , Leukocytes/metabolism , Male , Mice , Monocytes/drug effects , Monocytes/metabolism , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Restraint, Physical
9.
Basic Clin Pharmacol Toxicol ; 109(5): 365-71, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21624059

ABSTRACT

Emotional stress can be viewed as a cause of adverse circumstances that induces a wide range of biochemical and behavioural changes. Oxidative stress is a critical route of damage in various psychological stress-induced disorders such as depression. Antidepressants are widely prescribed to treat these conditions; however, no animal study has investigated the effect of selective serotonin reuptake inhibitors (SSRIs) on the levels of intracellular reactive oxygen species in peripheral blood leucocytes of stressed mice. In this study, mice were immobilized for a period of 6 hr. Fluoxetine (5 mg/kg of body-weight) was administered 30 min. before subjecting the animals to acute stress. The level of intracellular reactive oxygen species in leucocytes of the peripheral blood of stressed mice was investigated using a 2',7'-dichlorofluorescein diacetate probe, and the antioxidant response of fluoxetine was evaluated by superoxide dismutase, diaphorase, catalase and reduced glutathione. Our results show that restraint stress significantly increases the generation of reactive oxygen species in the peripheral defence cells. Treatment with fluoxetine partially reverses the adverse effects of stress. The improvement in cellular oxidative status may be an important mechanism underlying the protective pharmacological effects of fluoxetine, which are clinically observed in the treatment of depressive disorders.


Subject(s)
Fluoxetine/administration & dosage , Leukocytes/drug effects , Oxidative Stress/drug effects , Selective Serotonin Reuptake Inhibitors/administration & dosage , Stress, Psychological/drug therapy , Animals , Antioxidants/pharmacology , Catalase/metabolism , Fluoresceins/metabolism , Glutathione/metabolism , Immobilization , Male , Mice , Reactive Oxygen Species/metabolism , Stress, Psychological/metabolism , Superoxide Dismutase/metabolism
10.
Pharmacol Biochem Behav ; 97(2): 350-6, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20833196

ABSTRACT

The progression and development of multiple sclerosis (MS) has long been hypothesized to be associated with stress. Benzodiazepines have been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on their effects on MS, or experimental autoimmune encephalomyelitis (EAE), a model for human MS. We designed experiments conducted to ascertain whether alprazolam could modify the clinical, histological and neuroendocrine manifestations of acute EAE in Lewis rats exposed to a chronic auditory stressor. EAE was induced by injection of an emulsion of MBP and complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra. Stress application and treatment with drugs (placebo or alprazolam) were initiated 5days before inoculation and continued daily for the duration of the experiment (days 14 or 34 postinoculation).Our results show significant increases in the severity of neurological signs, the histological lesions of the spinal cord (inflammation), and the corticosterone plasmatic levels in stressed rats compared to those non-stressed ones. Treatment with alprazolam reversed the adverse effects of stress. These findings could have clinical implications in patients suffering from MS treated with benzodiazepines, so besides the psychopharmacological properties of alprazolam against stress, it has beneficial consequences on EAE.


Subject(s)
Alprazolam/pharmacology , Anti-Anxiety Agents/pharmacology , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Stress, Psychological/complications , Animals , Body Weight/drug effects , Corticosterone/blood , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/pathology , Freund's Adjuvant , Hypothalamo-Hypophyseal System/drug effects , Male , Mycobacterium tuberculosis/immunology , Noise/adverse effects , Rats , Rats, Inbred Lew , Spinal Cord/pathology
11.
Acta Odontol Scand ; 68(4): 239-47, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20507262

ABSTRACT

OBJECTIVE: To investigate the effects of resveratrol, a naturally occurring polyphenol, on the expression of vascular endothelial growth factor (VEGF) in human gingival fibroblast culture in response to vesicles and outer membrane proteins from periodontopathic bacteria. MATERIAL AND METHODS: Human gingival fibroblasts were stimulated with vesicles and outer membrane proteins from Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. In human gingival fibroblast cultures treated with or without resveratrol, VEGF production was evaluated by means of enzyme-linked immunosorbent assay and VEGF mRNA expression by means of reverse transcription polymerase chain reaction analysis. Vascular permeability enhancement was measured by the leakage of intravenously injected dye at the injection site of supernatant from cultures of human gingival fibroblasts stimulated by vesicles and outer membrane proteins. RESULTS: Resveratrol significantly inhibited the increased production of VEGF by human gingival fibroblasts in response to vesicles and outer membrane proteins from periodontopathic bacteria, as shown by the detection of these proteins and their mRNA in vitro. Moreover, resveratrol treatment significantly decreased vascular permeability enhancement induced by supernatant from human gingival fibroblast cultures stimulated by vesicles and outer membrane proteins. CONCLUSIONS: Overall, these findings suggest that resveratrol inhibits production of VEGF by stimulated human gingival fibroblasts and can inhibit vascular permeability, suggesting a therapeutic role for it in pathogenic bacteria-induced periodontal inflammation.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Gingiva/metabolism , Stilbenes/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Aggregatibacter actinomycetemcomitans/immunology , Analysis of Variance , Animals , Antioxidants/pharmacology , Bacterial Outer Membrane Proteins/immunology , Capillary Permeability/drug effects , Cattle , Cells, Cultured , Culture Media, Conditioned/pharmacology , Cytoplasmic Vesicles/immunology , DNA Damage , Female , Fibroblasts/metabolism , Gingiva/cytology , Guinea Pigs , Humans , Immunoenzyme Techniques , Porphyromonas gingivalis/immunology , RNA, Messenger/biosynthesis , Resveratrol , Statistics, Nonparametric , Vascular Endothelial Growth Factor A/biosynthesis
12.
Clin Vaccine Immunol ; 17(4): 668-73, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20130126

ABSTRACT

Psychological stress has been found to suppress cell-mediated immune responses that are important for limiting the proliferation of Candida albicans. Fluoxetine has been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on its effects on oral candidiasis. We designed experiments to evaluate the effects of fluoxetine on the development of oral candidiasis in Sprague-Dawley rats exposed to a chronic auditory stressor. Animals were submitted to surgical hyposalivation in order to facilitate the establishment and persistence of C. albicans infection. Stress application and treatment with drugs (placebo or fluoxetine) were initiated 7 days before C. albicans inoculation and lasted until the end of the experiments, on day 15 postinoculation. Establishment of C. albicans infection was evaluated on days 2 and 15 after inoculation. Tissue injury was determined by the quantification of the number and type (normal or abnormal) of papillae on the dorsal tongue per microscopic field. A semiquantitative scale was devised to assess the degree of colonization of the epithelium by fungal hyphae. Our results showed that stress exacerbates C. albicans infection in the tongues of rats. Significant increases in Candida counts, the percentage of the tongue's surface covered with clinical lesions, the percentage of abnormal papillae, and the colonization of the epithelium by hyphae were found in stressed rats compared to the nonstressed ones. Treatment with fluoxetine significantly reversed these adverse effects of stress. Besides the psychopharmacological properties of fluoxetine against stress, it has consequences for Candida infection.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Candida albicans/isolation & purification , Candidiasis, Oral/prevention & control , Fluoxetine/therapeutic use , Stress, Psychological/complications , Stress, Psychological/drug therapy , Animals , Candidiasis, Oral/microbiology , Colony Count, Microbial , Mouth Mucosa/pathology , Placebos/administration & dosage , Rats , Rats, Sprague-Dawley , Severity of Illness Index , Tongue/pathology
13.
Hum Exp Toxicol ; 26(8): 637-43, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17884951

ABSTRACT

The present experiment deals with the effects of amphetamine and cocaine on the development and course of experimental allergic encephalomyelitis (EAE) induced in Lewis rats. Rats were immunized at the age of eight weeks with purified myelin basic protein isolated from guinea pig brain in complete Freund's adjuvant. Drug administration and recording of EAE clinical signs was performed daily since day 1 post-immunization (PI). On day 14 and 28 PI, six rats per group were bled and sacrificed. Spinal cord was examined histologically for EAE lesions. In vivo administration of 0.5 and 1 mg/Kg of amphetamine or cocaine resulted in a dose-related enhancement of neurological and histological signs of acute EAE in comparison with control rats. Both drugs caused a reduction of latent period together with a delayed regression of neurological signs along with an increase in inflammation in the central nervous system in comparison with placebo. Human & Experimental Toxicology (2007) 26, 637-643.


Subject(s)
Amphetamine/toxicity , Behavior, Animal/drug effects , Central Nervous System Stimulants/toxicity , Cocaine/toxicity , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Spinal Cord/drug effects , Animals , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Freund's Adjuvant , Guinea Pigs , Male , Myelin Basic Protein , Rats , Rats, Inbred Lew , Spinal Cord/pathology , Time Factors
14.
Neurosci Lett ; 396(3): 247-51, 2006 Apr 03.
Article in English | MEDLINE | ID: mdl-16364545

ABSTRACT

We studied the effects of fluoxetine, a non-tricyclic antidepressant drug that selectively inhibits re-uptake of serotonin by presinaptic neurons in the brain, on cellular immune responses in mice exposed to a chronic auditory stressor. The natural killer (NK) cell activity was reduced after 4, 8, 12, 16 and 20 days of stress exposure with a partial recovery on days 16 and 20. Daily treatment with fluoxetine partially reversed these adverse effects of stress in a dose-dependent manner. Significant differences appeared when fluoxetine was administered at 2 mg/kg and maximum effect was reached at doses of 5 mg/kg. The capacity of T cells to generate cytotoxic T-lymphocytes (CTL) in mixed lymphocyte cultures and in vivo was reduced after 4 days of stress application and this effect was partially reduced when mice were injected with 5 mg/kg of fluoxetine. Nevertheless, in our experiments, fluoxetine did not significantly affect the cellular immunity in unstressed mice. In conclusion, fluoxetine seems to partially recover the adverse effects of chronic stress on cellular immune response.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Fluoxetine/pharmacology , Immunity, Cellular/drug effects , Stress, Physiological/immunology , Acoustic Stimulation/adverse effects , Analysis of Variance , Animals , Cell Count/methods , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Killer Cells, Natural/drug effects , Male , Mice , Mice, Inbred BALB C , Mitomycin/pharmacology , Spleen/pathology , Stress, Physiological/etiology , T-Lymphocytes, Cytotoxic/metabolism , Time Factors
15.
Psychopharmacology (Berl) ; 176(3-4): 233-8, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15164159

ABSTRACT

RATIONALE: Anxiety and depression are commonly encountered in patients with cancer and constitute risk and prognostic factors for the disease. Although previous findings do not support an overall association between the use of antidepressants and higher prevalence of cancer, results for serotonin uptake inhibitors are not entirely reassuring. OBJECTIVES: We evaluated the effects of nefazodone, a serotonin and norepinephrine (NE) reuptake inhibitor and 5-HT(2A) receptor antagonist antidepressant, on the appearance of breast cancer induced by mammary tumor virus (MTV) in mice, and on the development of lung metastases in rats injected intravenously with Walker 256 (W-256) carcinosarcoma cells. METHODS: Female C3H/He mice carrying the MTV were monitored for mammary tumor incidence and latent periods while being treated with a daily intraperitoneal injection with placebo or nefazodone. Rats were administered 10(4) W-256 cells, exposed to a chronic auditory stressor for 8 days, and then killed to evaluate metastatic nodules in the lungs. RESULTS: Although all of the mice were potential candidates for MTV-induced breast cancer, those treated with nefazodone were partially protected against adverse effects of stress induced by the daily administration of placebo on both parameters. Relative to placebo, nefazodone reduced the stress-induced increase in the number and percentage area of metastases in the frontal section through pulmonary hilus and increased the survival periods of rats given W-256 cells and exposed to a chronic auditory stressor. CONCLUSIONS: Our results provide evidence of the beneficial effects of nefazodone against the adverse effects of stress on tumor development and metastaticity in rodents, but did not show significant effects in unstressed rodents.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Neoplasms, Experimental/etiology , Neoplasms, Experimental/prevention & control , Stress, Psychological/complications , Stress, Psychological/pathology , Triazoles/pharmacology , Animals , Carcinoma 256, Walker/pathology , Male , Mammary Tumor Virus, Mouse , Mice , Mice, Inbred C3H , Piperazines , Rats , Rats, Sprague-Dawley , Retroviridae Infections/pathology , Tumor Cells, Cultured , Tumor Virus Infections/pathology
16.
Int Immunol ; 16(3): 489-99, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14978022

ABSTRACT

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the etiology of MS remains unknown, studies in experimental autoimmune encephalomyelitis (EAE) have suggested that foreign molecules, which show molecular mimicry with myelin antigens, may play an important role as causative agents of the human disease. In this study, we investigate the molecular mimicry between the extracellular Ig-like domain of the cow's milk protein butyrophilin (BTN) and the extracellular domain of myelin oligodendrocyte glycoprotein (MOG), a candidate autoantigen in MS. Interestingly, we found that as a result of a non-pathogenic cross-reactivity that is localized to a subdominant region of MOG, treatment of C57BL/6 mice with BTN either before or after immunization with MOG was shown to prevent and also suppress the clinical manifestations of EAE. BTN treatment resulted in a significant reduction in both proliferation and production of Th1-related cytokines (IFN-gamma, IL-2, IL-12 and granulocyte macrophage colony stimulating factor) in response to MOG. This specific inhibition was consistently associated with an up-regulation in IL-10 secretion. Furthermore, adoptive transfer of BTN-specific T cells prior to active immunization with MOG resulted in a transitory reduction of the clinical symptoms. Our results suggest that the clinical improvement associated with BTN treatment involved the combination of both anergy and regulatory cells secreting high levels of IL-10. In conclusion, we show that despite the traditional link between molecular mimicry and pathogenic immune response, environmental agents that share homology with autoantigens may also represent a source of cells with a protective phenotype.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immune Tolerance , Membrane Glycoproteins/immunology , Membrane Glycoproteins/therapeutic use , Molecular Mimicry/immunology , Myelin-Associated Glycoprotein/immunology , Animals , Butyrophilins , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cytokines/drug effects , Cytokines/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Female , Immunization , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Lymph Nodes/immunology , Mice , Mice, Inbred Strains , Multiple Sclerosis/immunology , Myelin Proteins , Myelin-Oligodendrocyte Glycoprotein , Peptides/immunology , Peptides/metabolism , Recombinant Proteins/immunology , Recombinant Proteins/pharmacology , Spleen/immunology
17.
J Autoimmun ; 21(4): 339-51, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14624757

ABSTRACT

Myelin oligodendrocyte glycoprotein (MOG) is a minor component of central nervous system myelin presumably implicated in the pathogenesis of Multiple Sclerosis (MS). Immunization with MOG leads to the development of Experimental Autoimmune Encephalomyelitis (EAE), the experimental model of MS. It has been suggested that its encephalitogenic potential may be due to the lack of MOG self-immune tolerance. To clarify this, we have generated a MOG deficient mouse (MOG(-/-)) strain. Surprisingly, MOG(35-55)specific proliferation and Th1-type cytokine production were markedly enhanced in MOG(-/-)mice compared to wild type control. Furthermore, adoptive transfer of MOG(35-55)specific T cells, isolated from MOG deficient mice, into wild-type recipients resulted in the development of a more severe disease, indicating a high capacity of MOG(-/-)T cells to initiate effector responses. Interestingly, T cell reactivity to overlapping MOG peptides in MOG(-/-)mice did not reveal new potential immunodominant epitopes in H-2(b)mice. Taken together, our data suggests that MOG self-tolerance modulates the encephalitogenic potential of autoreactive MOG T cells in the periphery.


Subject(s)
Autoimmunity/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Myelin-Associated Glycoprotein/deficiency , Myelin-Associated Glycoprotein/immunology , Adoptive Transfer , Animals , Cell Division , Cells, Cultured , Cytokines/metabolism , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gene Deletion , Humans , Mice , Mice, Knockout , Mice, Transgenic , Myelin Proteins/metabolism , Myelin-Associated Glycoprotein/genetics , Myelin-Associated Glycoprotein/metabolism , Myelin-Oligodendrocyte Glycoprotein , Rats , Rats, Sprague-Dawley , Spinal Cord/chemistry , Spleen/cytology , Spleen/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
18.
Neurosci Lett ; 342(1-2): 33-6, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12727311

ABSTRACT

Experimental allergic encephalomyelitis (EAE) is a T-cell inflammatory disease of the central nervous system (CNS) widely considered as an animal model of multiple sclerosis. In Lewis rats, myelin basic protein-complete Freund's adjuvant (MBP-CFA)-induced EAE is an acute monophasic disease from which animals recover fully. In our experiments, daily treatment (since day 1 after MBP-CFA inoculation) with the 5-hydroxytryptamine((1A)) (5-HT(1A)) receptor agonist (R)-(+)-8-hydroxy-2-(Dipropylamino)-tetralin (R(+)-8-OH-DPAT) resulted in a dose-related enhancement of neurological and histological signs in EAE-induced rats. This effect of R(+)-8-OH-DPAT was reduced by the co-administration of the 5-HT(1A) receptor antagonist (N-[2-(4-[2-mehoxyphenil]-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635) at the peak of the acute disease. Moreover, treatment with WAY100635 since inoculation resulted in a delayed onset of the first clinical signs, milder disease and earlier regression of neurological signs along with a decrease in inflammation in the CNS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Piperazines/pharmacology , Pyridines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Acute Disease , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/metabolism , Hypersensitivity , Male , Multiple Sclerosis/drug therapy , Piperazines/administration & dosage , Pyridines/administration & dosage , Rats , Rats, Inbred Lew , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin Antagonists/administration & dosage
19.
Life Sci ; 72(2): 173-83, 2002 Nov 29.
Article in English | MEDLINE | ID: mdl-12417251

ABSTRACT

We studied the effects of 1, 2, 5, 10 and 20 mg/kg of fluoxetine on the activity of phagocytosis in mice subjected to a chronic auditory stressor. Both the in vitro and in vivo activity of phagocytosis, measured using the zymosan-particle uptake method and the carbon clearance test, respectively, were reduced after 2, 4, 8 and 16 days of stress exposure. A partial recovery on the in vivo activity of phagocytosis was found on day 16th. Daily treatment with fluoxetine partially reversed the adverse effects of stress in a dose-dependent manner on both parameters but did not significantly affect the activity of phagocytosis in unstressed mice. Significant differences appeared when fluoxetine was administered at 2 mg/kg. Maximum effect was reached at 5 mg/kg.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Fluoxetine/pharmacology , Immunity, Cellular/drug effects , Phagocytosis/drug effects , Stress, Psychological/immunology , Adrenocorticotropic Hormone/blood , Algorithms , Animals , Dose-Response Relationship, Drug , In Vitro Techniques , Macrophages/drug effects , Macrophages/immunology , Male , Mice , Mice, Inbred BALB C , Noise/adverse effects , Time Factors
20.
Pharmacol Biochem Behav ; 73(3): 689-96, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12151045

ABSTRACT

Late-onset ethanol (EtOH) consumption is related to life and social stressors of aging. The stress system (hypothalamic-pituitary-adrenal, HPA, axis) coordinates the adaptive response of the organism to stressors, but age-related deficits in HPA function seem to be associated with disorders such as late-onset EtOH consumption, anxiety and depression. In the present study, we examined whether HPA dysfunction is associated with stress-related EtOH consumption in aged rats and whether the treatment with nefazodone hydrochloride, a phenylpiperazine antidepressant, partially reverses the adverse effects of isolation (ISOL) stress. The animals were offered two-bottle choice consumption of 0.2% saccharin and 10% EtOH/0.2% saccharin, and then exposed to 4 days of ISOL stress on an irregular, unpredictable schedule. ISOL stress-induced increases in corticosterone secretion and EtOH consumption both during and following the stress (recovery period) in aged rats. Nevertheless, this effect at the recovery period was not evident in young stressed rats. Nefazodone caused a significant decrease in plasma corticosterone levels and EtOH consumption. The attenuation of stress-induced corticosterone by nefazodone was correlated with reduced EtOH consumption. These findings link the effect of ISOL stress to the induction of voluntary EtOH consumption following the end of the stressor and the limitation of aged HPA to down-regulated corticosterone.


Subject(s)
Alcohol Drinking/prevention & control , Alcohol Drinking/psychology , Antidepressive Agents, Second-Generation/pharmacology , Social Isolation , Stress, Psychological/psychology , Triazoles/pharmacology , Aging/psychology , Animals , Anxiety/drug therapy , Anxiety/psychology , Corticosterone/blood , Female , Hippocampus/pathology , Piperazines , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Stress, Psychological/drug therapy , Stress, Psychological/pathology
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