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1.
Braz. j. infect. dis ; 24(2): 150-159, Mar.-Apr. 2020. tab, graf
Article in English | LILACS, ColecionaSUS | ID: biblio-1132431

ABSTRACT

ABSTRACT Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Quinazolines/pharmacology , Azepines/pharmacology , Virus Activation/drug effects , HIV Infections/virology , HIV-1/drug effects , Niacinamide/pharmacology , Methyltransferases/antagonists & inhibitors , Piperazines/pharmacology , Leukocytes, Mononuclear/virology , CD4-Positive T-Lymphocytes , Gene Expression Regulation, Viral , Virus Latency , Viral Load/drug effects , Viral Tropism/drug effects
2.
Biol. Res ; 50: 19, 2017. graf
Article in English | LILACS | ID: biblio-950871

ABSTRACT

BACKGROUND: Bromodomain-containing protein 4 (BRD4) inhibition is a new therapeutic strategy for many malignancies. In this study, we aimed to explore the effect of BRD4 inhibition by JQ1 on in vitro cell growth, migration and invasion of salivary adenoid cystic carcinoma (SACC). METHODS: The human normal epithelial cells and SACC cells (ACC-LM and ACC-83) were treated with JQ1 at concentrations of 0, 0.1, 0.5 or 1 µM. Cell Counting Kit-8 (CCK-8) assay was performed to evaluate cell proliferation. Cell apoptosis and cell cycle distribution was evaluated by Flow cytometry. Immunofluorescence staining was used to examine the expression of BRD4 in SACC cells. The quantitative real-time polymerase chain reaction (qRT-PCR) assay and western blot assay were performed to examine messenger RNA (mRNA) and protein levels in SACC cells. Wound- healing assay and transwell assay were used to evaluate the activities of migration and invasion of SACC cells. RESULTS: JQ1 exhibits no adverse effects on proliferation, cell cycle and cell apoptosis of the normal human epithelial cells, while suppressed proliferation and cell cycle, and induced apoptosis of SACC cells, down-regulated the mRNA and protein levels of BRD4 in SACC cells, meanwhile reduced protein expressions of c-myc and BCL-2, two known target genes of BRD4. Moreover, JQ1 inhibited SACC cell migration and invasion by regulating key epithelial-mesenchymal transition (EMT) characteristics including E-cadherin, Vimentin and Twist. CONCLUSIONS: BRD4 is an important transcription factor in SACC and BRD4 inhibition by JQ1 may be a new strategy for SACC treatment.


Subject(s)
Humans , Azepines/pharmacology , Transcription Factors/antagonists & inhibitors , Triazoles/pharmacology , Salivary Gland Neoplasms/drug therapy , Nuclear Proteins/antagonists & inhibitors , Cell Movement/drug effects , Carcinoma, Adenoid Cystic/drug therapy , Cell Proliferation/drug effects , Neoplasm Invasiveness/pathology , Salivary Gland Neoplasms/pathology , Down-Regulation , Carcinoma, Adenoid Cystic/pathology , Cell Cycle Proteins , Cell Line, Tumor , Real-Time Polymerase Chain Reaction
3.
Dental press j. orthod. (Impr.) ; 20(1): 59-65, Jan-Feb/2015. tab, graf
Article in English | LILACS | ID: lil-741448

ABSTRACT

OBJECTIVE: The aim of the present study was to assess the diagnostic value of a laser scanner developed to determine the coordinates of clinical bracket points and to compare with the results of a coordinate measuring machine (CMM). METHODS: This diagnostic experimental study was conducted on maxillary and mandibular orthodontic study casts of 18 adults with normal Class I occlusion. First, the coordinates of the bracket points were measured on all casts by a CMM. Then, the three-dimensional coordinates (X, Y, Z) of the bracket points were measured on the same casts by a 3D laser scanner designed at Shahid Beheshti University, Tehran, Iran. The validity and reliability of each system were assessed by means of intraclass correlation coefficient (ICC) and Dahlberg's formula. RESULTS: The difference between the mean dimension and the actual value for the CMM was 0.0066 mm. (95% CI: 69.98340, 69.99140). The mean difference for the laser scanner was 0.107 ± 0.133 mm (95% CI: -0.002, 0.24). In each method, differences were not significant. The ICC comparing the two methods was 0.998 for the X coordinate, and 0.996 for the Y coordinate; the mean difference for coordinates recorded in the entire arch and for each tooth was 0.616 mm. CONCLUSION: The accuracy of clinical bracket point coordinates measured by the laser scanner was equal to that of CMM. The mean difference in measurements was within the range of operator errors. .


OBJETIVO: o objetivo do presente estudo foi avaliar o valor diagnóstico de um scanner a laser desenvolvido para determinar as coordenadas dos pontos de colagem de braquetes, comparando seus resultados aos resultados obtidos com uma máquina de medição coordenada (MMC). MÉTODOS: esse estudo experimental diagnóstico foi conduzido com modelos ortodônticos obtidos a partir da arcada superior de 18 pacientes adultos, com oclusão normal de Classe I. Inicialmente, as coordenadas dos pontos de colagem de braquetes de todos os modelos foram mensuradas por uma MMC. Em seguida, as coordenadas tridimensionais (X, Y, Z) dos pontos foram mensuradas nos mesmos modelos por um scanner a laser 3D, desenvolvido na Universidade de Shahid Beheshti. A eficácia e confiabilidade dos dois sistemas foram avaliadas pelo Coeficiente de Correlação Intraclasse (CCI) e pela fórmula de Dahlberg. RESULTADOS: a diferença entre a média da dimensão mensurada pela MMC e o valor real obtido foi de 0,0066mm (IC 95%: 69,98340 - 69,99140). A diferença média para o scanner a laser foi de 0,107 ± 0,133 (95% IC: -0,002 - 0,24). Em cada método, as diferenças não foram significativas. Ao comparar os dois métodos, o CCI gerou um valor de 0,998 para a coordenada X e de 0,996 para a coordenada Y. A diferença média para as coordenadas registradas em cada dente da arcada foi de 0,616mm. CONCLUSÃO: a precisão das coordenadas do ponto de colagem dos braquetes foi a mesma no scanner a laser e na MMC. A diferença média entre as medições manteve-se dentro dos limites de erros operacionais. .


Subject(s)
Animals , Humans , Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases/genetics , Hidradenitis Suppurativa/genetics , Presenilin-1/genetics , Alanine/analogs & derivatives , Alanine/pharmacology , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Azepines/pharmacology , Hidradenitis Suppurativa/enzymology , Mutation, Missense
4.
Braz. j. med. biol. res ; 47(10): 826-833, 10/2014. graf
Article in English | LILACS | ID: lil-722174

ABSTRACT

O-GlcNAcylation is a modification that alters the function of numerous proteins. We hypothesized that augmented O-GlcNAcylation levels enhance myosin light chain kinase (MLCK) and reduce myosin light chain phosphatase (MLCP) activity, leading to increased vascular contractile responsiveness. The vascular responses were measured by isometric force displacement. Thoracic aorta and vascular smooth muscle cells (VSMCs) from rats were incubated with vehicle or with PugNAc, which increases O-GlcNAcylation. In addition, we determined whether proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation. PugNAc enhanced phenylephrine (PE) responses in rat aortas (maximal effect, 14.2±2 vs 7.9±1 mN for vehicle, n=7). Treatment with an MLCP inhibitor (calyculin A) augmented vascular responses to PE (13.4±2 mN) and abolished the differences in PE-response between the groups. The effect of PugNAc was not observed when vessels were preincubated with ML-9, an MLCK inhibitor (7.3±2 vs 7.5±2 mN for vehicle, n=5). Furthermore, our data showed that differences in the PE-induced contractile response between the groups were abolished by the activator of AMP-activated protein kinase (AICAR; 6.1±2 vs 7.4±2 mN for vehicle, n=5). PugNAc increased phosphorylation of myosin phosphatase target subunit 1 (MYPT-1) and protein kinase C-potentiated inhibitor protein of 17 kDa (CPI-17), which are involved in RhoA/Rho-kinase-mediated inhibition of myosin phosphatase activity. PugNAc incubation produced a time-dependent increase in vascular phosphorylation of myosin light chain and decreased phosphorylation levels of AMP-activated protein kinase, which decreased the affinity of MLCK for Ca2+/calmodulin. Our data suggest that proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation, favoring vascular contraction.


Subject(s)
Animals , Male , Muscle, Smooth, Vascular/physiology , Myosin Light Chains/metabolism , Protein Processing, Post-Translational/physiology , Vasoconstriction/physiology , Aorta, Thoracic , Acetylglucosamine/analogs & derivatives , Acetylglucosamine/pharmacology , Acylation/drug effects , Acylation/physiology , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Azepines/pharmacology , Blotting, Western , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myosin-Light-Chain Kinase/metabolism , Myosin-Light-Chain Phosphatase/metabolism , Oxazoles/pharmacology , Oximes/pharmacology , Phenylcarbamates/pharmacology , Phenylephrine/agonists , Phosphorylation/drug effects , Phosphorylation/physiology , Rats, Wistar , Ribonucleotides/pharmacology , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , beta-N-Acetylhexosaminidases/antagonists & inhibitors
5.
Article in English | WPRIM | ID: wpr-15693

ABSTRACT

In adipocytes, insulin stimulates glucose transport primarily by promoting the translocation of GLUT4 to the plasma membrane. Requirements for Ca2+/ calmodulin during insulin-stimulated GLUT4 translocation have been demonstrated; however, the mechanism of action of Ca2+ in this process is unknown. Recently, myosin II, whose function in non-muscle cells is primarily regulated by phosphorylation of its regulatory light chain by the Ca2+/calmodulin-dependent myosin light chain kinase (MLCK), was implicated in insulin-stimulated GLUT4 translocation. The present studies in 3T3- F442A adipocytes demonstrate the novel finding that insulin significantly increases phosphorylation of the myosin II RLC in a Ca2+-dependent manner. In addition, ML-7, a selective inhibitor of MLCK, as well as inhibitors of myosin II, such as blebbistatin and 2,3-butanedione monoxime, block insulin- stimulated GLUT4 translocation and subsequent glucose transport. Our studies suggest that MLCK may be a regulatory target of Ca2+/calmodulin and may play an important role in insulin-stimulated glucose transport in adipocytes.


Subject(s)
Mice , Animals , Protein Transport/drug effects , Phosphorylation , Naphthalenes/pharmacology , Myosin-Light-Chain Kinase/antagonists & inhibitors , Myosin Type II/metabolism , Insulin/pharmacology , Glucose Transporter Type 4/metabolism , Enzyme Inhibitors/pharmacology , Dose-Response Relationship, Drug , Calmodulin/antagonists & inhibitors , Azepines/pharmacology , Adipocytes/cytology , 3T3 Cells
6.
Alexandria Journal of Pharmaceutical Sciences. 1997; 11 (1): 49-58
in English | IMEMR | ID: emr-43833
7.
Indian J Exp Biol ; 1994 Mar; 32(3): 172-5
Article in English | IMSEAR | ID: sea-60377

ABSTRACT

Possible involvement of dopaminergic (DAergic) system in forced swimming-induced immobility (despair behaviour) was investigated in mice. B-HT 920 (0.05 and 0.1 mg/kg), a post-synaptic DAergic agonist, produced a dose dependent reduction in immobility period, which was sensitive to blockade by haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). This effect was also blocked by alpha 2 antagonist yohimbine (5 mg/kg). SKF 38393 (5 mg/kg), a D1-DA agonist potentiated the action of B-HT 920. Reserpinization (2 mg/kg, 24 hr prior) produced despair immobility in mice. When a low dose of B-HT 920 (0.05 mg/kg) was given to reserpinized animals, the duration of immobility period was further increased. But on the other hand, a higher dose (0.1 mg/kg) of it reduced reserpine-induced immobility. Desipramine (5 and 10 mg/kg), elicited a dose dependent reduction in the immobility period, which was sensitive to blockade by sulpiride (100 mg/kg). Desipramine (10 mg/kg) showed a diphasic response in combination with B-HT 920, i.e., a potentiation of the response due to a low dose of B-HT 920 (0.05 mg/kg) and an antagonism of the response due to a higher dose of B-HT 920 (0.1 mg/kg), respectively. SKF 38393 (5 mg/kg), potentiated the action of desipramine (5 mg/kg). SKF 38393 (5 mg/kg) further potentiated the action of desipramine (5 mg/kg) and B-HT 920 (0.05 mg/kg). These observations suggests that B-HT 920 reduces behavioural immobility by DAergic mechanism and desipramine also modulates D2-DA receptors in its anti-depressant action.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Antidepressive Agents/pharmacology , Azepines/pharmacology , Desipramine/pharmacology , Drug Interactions , Escape Reaction/drug effects , Female , Haloperidol/pharmacology , Male , Mice , Motor Activity/drug effects , Receptors, Dopamine/classification , Reserpine/pharmacology , Sulpiride/pharmacology , Swimming , Yohimbine/pharmacology
8.
Indian J Exp Biol ; 1994 Mar; 32(3): 176-9
Article in English | IMSEAR | ID: sea-61727

ABSTRACT

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Azepines/pharmacology , Benzazepines/pharmacology , Desipramine/pharmacology , Dioxanes/pharmacology , Dopamine/pharmacology , Female , Haloperidol/pharmacology , Idazoxan , Male , Muscle Contraction/drug effects , Prazosin/pharmacology , Rats , Receptors, Adrenergic/drug effects , Receptors, Dopamine/classification , Reserpine/pharmacology , Sulpiride/pharmacology , Yohimbine/pharmacology
9.
Bulletin of Faculty of Pharmacy-Cairo University. 1993; 31 (1): 55-61
in English | IMEMR | ID: emr-95504
10.
Indian J Exp Biol ; 1991 Nov; 29(11): 1084-6
Article in English | IMSEAR | ID: sea-62279

ABSTRACT

Effect of B-HT 920, a selective alpha 2 adrenoceptor agonist, was studied on ouabain induced cardiac arrhythmias and cardiac arrest in guinea pigs. Ventricular premature beats, ventricular tachyarrhythmias and cardiac arrest were induced in anaesthetized guinea pigs by slow infusion of ouabain. B-HT 920 accorded significant protection to guinea pigs against ouabain induced arrhythmias. Yohimbine inhibited the antiarrhythmic effect of B-HT 920 significantly. It is concluded that the protective effect of B-HT 920 against ouabain induced cardiac arrhythmias and cardiac arrest is mediated through the stimulation of alpha 2 adrenoceptors.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Animals , Arrhythmias, Cardiac/chemically induced , Azepines/pharmacology , Female , Guinea Pigs , Heart/drug effects , Heart Arrest/chemically induced , Male , Ouabain/toxicity
11.
Indian J Exp Biol ; 1991 Feb; 29(2): 123-6
Article in English | IMSEAR | ID: sea-57114

ABSTRACT

The present study attempts to demonstrate D1/D2 dopamine (DA) receptor interactions during stereotyped behaviour in mice. B-HT 920 [2-amino-6-allyl-5, 6, 7, 8-tetrahydro-4H-thiazolo-(4, 5-d)-azepine] (0.05-1.0 mg/kg), a selective D2-DA agonist, induced mild per se stereotypy consisting mainly of sniffing and rearing responses. Apomorphine, a mixed D1/D2 agonist, also produced typical stereotypic response in mice. The stereotypic response of B-HT 920 was blocked by D2-DA antagonist, sulpiride (50 mg/kg). The effect of apomorphine was not influenced by co-treatment with SKF 38393. Simultaneous administration of B-HT 920 (0.1-0.5 mg/kg) with SKF 38393 (5 mg/kg), a selective D1-DA agonist, elicited dramatic increase in stereotyped behaviours in naive as well as in 24 hr reserpinised (2 mg/kg) mice. Co-treatment of apomorphine (0.5 mg/kg) with B-HT 920 (0.1, 0.25 mg/kg) also resulted in a clearly synergistic effect on stereotyped behaviour. These potentiated responses were reduced or blocked by haloperidol, a D2-DA antagonist. The data suggest that in presence of concomitant stimulation of D1-DA receptors. B-HT 920 exhibits full expression of postsynaptic D2-DA receptor mediated behavioural effects.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Azepines/pharmacology , Female , Male , Mice , Receptors, Dopamine/drug effects , Receptors, Dopamine D1 , Receptors, Dopamine D2
12.
Mem. Inst. Oswaldo Cruz ; 86(supl.2): 129-131, 1991. ilus, tab
Article in English | LILACS | ID: lil-623954

ABSTRACT

The potential participation of PAF-acether (PAF) on the paw oedema triggered by enterolobin was investigated. Intraplantar injections of enterolobin )5-20 µg/paw) yielded a dose response curve for edema which appeared after 30 min, peaked in the interval between 2-4 h and faded after 24h. The pre-treatment with BN 52021, but not with other PAF antagonists such as PCA 4248 or WEB 2086, significantly blocked enterolobin-induced oedema. To clarify better the discrepant results obtained with the PAF antagonists, desensitization to PAF was performed. The oedema triggered by enterolobin was not modified in paf desensitized animals. It was concluded that the paw inflammation induced by enterolobin does not require PAF mechanism.


Subject(s)
Animals , Male , Rats , Plant Proteins/antagonists & inhibitors , Plant Proteins/toxicity , Azepines/pharmacology , Triazoles/pharmacology , Dihydropyridines/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Activating Factor/physiology , Rats, Wistar , Ginkgolides , Diterpenes
13.
Braz. j. med. biol. res ; 22(9): 1151-4, 1989. ilus
Article in English | LILACS | ID: lil-83193

ABSTRACT

The chemotactic activity of PAF-acether was compared with that of tetrapeptide eosinophil chemotactic factors of anaphylaxis (ECF-A, Ala-Gly-Ser Glu and Val-Gly-Ser-Glu) using eosinophils obtained from the peritoneal cavity of normal rats. Cells were isolated by separation over discontinuous metrizamide gradients which resulted in eosinophil suspensions of 80 to 90% purity. PAF-acether produced 7-fold greater than the maximal activity obtained with the ECF-A-tetrapeptides. BN 52021 and WEB 2086 inhibited PAF-acether-induced eosinophil chemotaxis in a dose-dependent manner, suggesting that this phenomenon is mediated by specific PAF-acether receptors


Subject(s)
Rats , Animals , Male , Eosinophils/physiology , Platelet Activating Factor/antagonists & inhibitors , Chemotactic Factors, Eosinophil/pharmacology , In Vitro Techniques , Peritoneal Cavity/cytology , Azepines/pharmacology , Cell Movement , Chemotaxis , Lactones/pharmacology , Rats, Inbred Strains , Triazines/pharmacology
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