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1.
Adv Exp Med Biol ; 1200: 71-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471795

RESUMO

The ability to adapt to changing environmental conditions is critical for any species to survive. Many environmental changes occur too rapidly for an organism's genome to adapt in time. Accordingly, being able to modify either its own phenotype, or the phenotype of its offspring to better suit future anticipated environmental conditions could afford an organism a significant advantage. However, a range of animal models and human epidemiological data sets are now showing that environmental factors such as changes in the quality or quantity of an individual's diet, temperature, stress or exposure to pollutants can all adversely affect the quality of parental gametes, the development of the preimplantation embryo and the health and wellbeing of offspring over multiple generations. This chapter will examine transgenerational effects of both maternal and paternal environmental factors on offspring development and wellbeing in both human and animal model studies. Changes in the epigenetic status of either parental or grand-parental gametes provide one candidate mechanism through which the impacts of environmental experience can be passed from one generation to another. This chapter will therefore also focus on the impact of parental and grand-parental diet on epigenetic transgenerational inheritance and offspring phenotype.


Assuntos
Adaptação Biológica/genética , Dieta , Meio Ambiente , Epigênese Genética , Animais , Humanos , Modelos Animais , Fenótipo
2.
Braz Oral Res ; 33: e086, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31483052

RESUMO

Treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Quitosana/farmacologia , Maxila/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Quitosana/uso terapêutico , Preparações de Ação Retardada , Feminino , Humanos , Maxila/patologia , Microesferas , Modelos Animais , Hormônio Paratireóideo/uso terapêutico , Poloxâmero/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Ácido Zoledrônico/efeitos adversos
4.
Rev Soc Bras Med Trop ; 52: e20180526, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31508780

RESUMO

INTRODUCTION: Crotalus envenomations cause serious complications and can be fatal without appropriate treatment. Venom isoforms present and inter/intraspecific variations in the venom composition can result in different symptoms presented by bites by snakes from the same species but from different geographical regions. We comparatively evaluated the local and systemic effects caused by Crotalus durissus terrificus (Cdt), C.d. collilineatus (Cdcolli), and C.d. cascavella (Cdcasc) envenomation. METHODS: Venom chromatography was performed. Proteolytic, phospholipase, and LAAO activities were analyzed. Edema, myotoxicity, hepatotoxicity, nephrotoxicity, and coagulation alterations were evaluated. RESULTS: The venom SDS-PAGE analyses found the presence of convulxin, gyroxin, crotoxin, and crotamine in Cdt and Cdcolli venoms. Crotamine was not present in the Cdcasc venom. Cdt, Cdcollli, and Cdcasc venoms had no proteolytic activity. Only Cdcasc and Cdt venoms had phospholipase activity. LAAO activity was observed in Cdcolli and Cdcasc venoms. Cdcolli and Cdcasc venoms caused 36.7% and 13.3% edema increases, respectively. Cdt venom caused a 10% edema induction compared to those by other venoms. All venoms increased TOTAL-CK, MB-CK, and LDH levels (indicating muscle injury) and ALT, AST, GGT, and ALP levels (markers of liver damage) and were able to induce a neuromuscular blockade. Urea and creatinine levels were also altered in both plasma and urine, indicating kidney damage. Only Cdcolli and Cdcasc venoms increased TAPP and TAP. CONCLUSIONS: Together, these results allow us to draw a distinction between local and systemic effects caused by Crotalus subspecies, highlighting the clinical and biochemical effects produced by their respective venoms.


Assuntos
Venenos de Crotalídeos/toxicidade , Crotalus/classificação , Edema/induzido quimicamente , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fosfatase Alcalina/sangue , Fosfatase Alcalina/efeitos dos fármacos , Animais , Creatina Quinase/sangue , Creatina Quinase/efeitos dos fármacos , Creatinina/sangue , Edema/patologia , Eletroforese em Gel de Poliacrilamida , Rim/patologia , L-Lactato Desidrogenase/sangue , L-Lactato Desidrogenase/efeitos dos fármacos , Fígado/patologia , Camundongos , Modelos Animais , Transaminases/sangue , Transaminases/efeitos dos fármacos , Ureia/sangue
5.
Acta Cir Bras ; 34(7): e201900709, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31531529

RESUMO

PURPOSE: To develop a new low-cost, easy-to-make and available training model using chickens' intestine for infant intestinal anastomosis. METHODS: Segments of chicken intestine were used to create an intestinal anastomosis simulator. We tried to perform an end-to-end, end-to-side and side-to-side anastomosis. Handsewn sutured anastomosis were performed in single layered with interrupted prolene 5-0 suture. The parameters analyzed were cost, intestine's diameter and length, anastomosis patency and flow-through and leakage amount. RESULTS: In all cases it was possible to make the anastomosis in double layered without difficulties, different from the usual ones. There was a positive patency at all anastomoses after the end of the procedure, with no need for reinterventions. CONCLUSION: The new training model using chickens' intestine for infant intestinal anastomosis is low-cost, easy-to-make and easy available.


Assuntos
Anastomose Cirúrgica/educação , Intestinos/cirurgia , Pediatria/educação , Anastomose Cirúrgica/instrumentação , Anastomose Cirúrgica/métodos , Animais , Galinhas , Criança , Humanos , Modelos Animais , Técnicas de Sutura
6.
Acta Cir Bras ; 34(6): e201900601, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432992

RESUMO

PURPOSE: To evaluate PBS®MCIMMO cement in the filling of bone defects. METHODS: Thirty-six adult male Wistar rats were divided into three groups of twelve individuals each (group 1, group 2 and group 3). In all groups, a bone failure in the femur was induced, 2.0 mm wide and 7.0 mm deep. In group 1, the PBS®MCIMMO cement was applied to the bone defect produced and a titanium implant (CONNECTION®) 1.5 mm thick and 6 mm long was installed. In group 2, only the PBS® CIMMO cement was installed. In group 3, only bone failure was performed. Kruskal Wallis tests were performed to compare the mean area among the three groups. RESULTS: In all comparisons, significance was observed for group 2 (p = 0.0014-0.0026). CONCLUSION: The PBS®CIMMO cement induced bone neoformation, and integration between the newly formed bone, cement, and implant was observed.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Cimentos para Ossos , Regeneração Óssea/fisiologia , Substitutos Ósseos/administração & dosagem , Cerâmica , Fêmur/cirurgia , Teste de Materiais , Animais , Estudos Longitudinais , Masculino , Modelos Animais , Estudos Prospectivos , Ratos , Ratos Wistar
7.
Acta Cir Bras ; 34(6): e201900610, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31433001

RESUMO

PURPOSE: To identify whether the colon mucosa is affected by ten days of gastric restriction in an animal model. METHODS: An experimental model of gastric restriction was devised using rats. The animals were submitted to surgical gastrostomy, and a cylindrical loofah was inserted into the stomach. We studied 30 adult male Wistar rats divided into three groups: the stomach restriction group (R10); the sham group (S10), which underwent the same procedure except for the loofah insertion; and the control group (C10). The expression of neutral and acid mucins was evaluated using histochemical techniques. Goblet cells and protein content were compared between groups using generalized estimation equations (GEEs). Bonferroni's multiple comparison was applied to identify differences between the groups. All tests considered a 5% significance level. RESULTS: There was an increased expression of neutral mucins, acid mucins and goblet cells in the R10 group. Collagen was also enhanced in the R10 group. CONCLUSION: The colon mucosa is affected by ten days of gastric restriction in an animal model, increasing neutral mucins, acid mucins and collagen content with trophic maintenance.


Assuntos
Privação de Alimentos , Mucosa Intestinal/metabolismo , Mucinas/metabolismo , Animais , Colo , Gastrostomia , Mucosa Intestinal/patologia , Masculino , Modelos Animais , Ratos , Ratos Wistar , Fatores de Tempo
8.
Yi Chuan ; 41(8): 686-702, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31447420

RESUMO

Spermatogonial stem cells (SSCs) are male germline stem cells that reside in the basement membrane of the seminiferous tubule in the testis. SSCs are characterized by their capability of self-renewal to maintain the stem cell pool throughout the lifespan and commitments to germ line after puberty, thus transmitting the genetic information from parents to the SSC-derived progenies. SSCs can be isolated from testis, propagated in vitro, and induced to differentiate into varied germ cells. Although significant progress has been made in the field of rodent SSCs, the SSCs of large animals have advanced slowly. Studies on SSCs of large animal models can offer insights into the physiological and pathological mechanism of human reproduction. Moreover, SSCs of agricultural large animals can be used as an essential tool for multiplication of elite animal individuals, and generation of genetically modified livestock with valuable economic traits. In this review, we summarize the recent progress on SSCs of large animal models for agricultural and medical purposes, and discuss the present problems and future prospects. This review can give an overall view of large animal SSCs as respect to their applications in novel alternative reproductive technologies, generation of transgenic animals, treatment of male infertility and regenerative medicine.


Assuntos
Espermatogônias/citologia , Células-Tronco/citologia , Animais , Animais Geneticamente Modificados , Humanos , Infertilidade Masculina , Masculino , Modelos Animais , Testículo/citologia
9.
J Forensic Leg Med ; 67: 37-48, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419763

RESUMO

Previous studies have begun to characterize the microbial community dynamics of the skin, soil, gut, and oral cavities of decomposing remains. One area that has yet to be explored in great detail is the microbiome of the fly larval mass, the community of immature flies that plays a significant role in decomposition. The current study aimed to characterize the microbiology and chemistry of larval masses established on pig (Sus scrofa domesticus) carcasses and to determine if these characteristics have potential as temporal evidence. Carcasses (n = 3) were decomposed on the soil surface of a tropical habitat on Oahu, Hawaii, USA and sampled over three days at 74 h, 80 h, 98 h, 104 h, 122 h, and 128 h (∼85-142 Accumulated Degree Days) postmortem. Larval masses were analyzed via high-throughput 16S rRNA sequencing and in situ chemical measurements (pH, temperature, oxidation-reduction potential). A trend was observed that resulted in three distinct microbial communities (pre-98 h, 98 h, and post-98 h). The oxidation-reduction potential (Eh) of larval masses apparently regulated microbial community structure with the most negative Eh being associated with the least rich and diverse microbial communities. Overall, a significant interaction between time and taxa was observed, particularly with bacterial phyla Firmicutes and Proteobacteria. The current results provide new insight into the microbial community and chemical parameters of larval masses and indicate a temporal shift that could be further studied as a PMI estimator.


Assuntos
Comportamento Alimentar , Larva/química , Larva/microbiologia , Microbiota , Mudanças Depois da Morte , Animais , Bactérias/genética , Entomologia , Patologia Legal , Hawaii , Concentração de Íons de Hidrogênio , Modelos Animais , Oxirredução , RNA Ribossômico 16S , Análise de Sequência de RNA , Suínos
10.
Am J Orthod Dentofacial Orthop ; 156(2): 193-202, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375229

RESUMO

OBJECTIVES: To evaluate whether the effects on the mandibular condylar cartilage (MCC) and subchondral bone are transient of botulinum neurotoxin (Botox) injection into the masseter muscle. METHODS: Botox (0.3 U) was injected into the right masseter of 6-week-old female mice (C57BL/6; n = 16). In addition, 16 mice were used as control and received no injections. Experimental and matching control mice were killed 4 or 8 weeks after the single Botox injection. Mandibles and mandibular condyles were analyzed by means of microscopic computed tomography (microCT) and histology. Sagittal sections of condyles were stained for tartrate-resistant acid phosphatase (TRAP), toluidine blue, 5-ethynyl-2'-deoxyuridine (EdU), and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. RESULTS: Bone volume fraction was significantly decreased on the subchondral bone of the Botox-injected side, compared with the control side and control mice, 4 and 8 weeks after injection. Furthermore, histologic analysis revealed decrease in mineralization, cartilage thickness, TRAP activity, and EdU-positive cells in the MCC of the Botox-injected side 4 and 8 weeks after injection. CONCLUSIONS: The effects on the MCC and subchondral bone of Botox injection into the masseter muscle persisted for 8 weeks after injection and were not considered to be transient.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Côndilo Mandibular/efeitos dos fármacos , Músculo Masseter/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Injeções , Masculino , Mandíbula , Côndilo Mandibular/diagnóstico por imagem , Côndilo Mandibular/patologia , Músculo Masseter/diagnóstico por imagem , Músculo Masseter/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Articulação Temporomandibular
11.
Toxicol Lett ; 314: 181-186, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31404594

RESUMO

The cytochrome P450 enzyme (CYP) family includes key enzymes for the metabolism of drugs and xenobiotics. Several animal models have been used to determine the metabolite profile of specific drugs. Among these are porcine microsomes prepared from Göttingen minipigs. However, CYP expression profile in microsomes from this pig breed is unknown. In the present study, we determined the mRNA and protein profiles of a comprehensive selection of CYPs in microsomes prepared from male and female Göttingen minipigs. Using RT-PCR, western blotting and mass spectroscopy, we found that the expression levels of CYP1A, CYP2A and CYP2E1 were significantly higher in females than males. Moreover, some of the transcription factors controlling CYP transcription also showed a sex-dependent expression pattern. Conversely, expression of CYP2B, CYP2D and CYP3A was comparable between sexes. The overall CYP expression distribution showed high similarity with what previously been reported in humans. In conclusion, our results suggest that Göttingen minipigs are a reliable model for studying CYPs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/enzimologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Isoenzimas , Masculino , Microssomos/enzimologia , Modelos Animais , Fatores Sexuais , Especificidade por Substrato , Suínos , Porco Miniatura
12.
Br J Anaesth ; 123(4): 488-496, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383363

RESUMO

BACKGROUND: General anaesthetics affect loss of consciousness by disrupting information-passing and integration within thalamo-cortical (TC) networks. Feedback cortical connections that carry internally generated signals such as expectation and attention appear more sensitive to anaesthesia than feedforward signals. However, direct evidence for this effect in non-primary cortex is lacking. In addition, direct comparisons between TC core and matrix, and between cortico-cortical (CC) feedforward and feedback responses have not been reported. METHODS: We investigated the disruption of synaptic responses by isoflurane of four distinct afferent pathways to non-primary neocortex. We independently activated TC core and matrix and reciprocal CC (feedforward and feedback) pathways using optogenetic techniques, and compared the relative sensitivity of synaptic responses to isoflurane. RESULTS: Under control conditions, activation of axon terminals of all pathways evoked postsynaptic currents (recorded extracellularly) and postsynaptic potentials in pyramidal neurones. CC feedback responses were substantially more sensitive to isoflurane (0 to 0.53 mM) compared with TC core, TC matrix, or CC feedforward pathways. CONCLUSION: Differential sensitivity of CC feedback synaptic responses to isoflurane in a clinically relevant range suggests a role for disruption of these afferents in the hypnotic effects of anaesthetic agents.


Assuntos
Anestésicos Inalatórios/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Isoflurano/farmacologia , Neocórtex/efeitos dos fármacos , Animais , Camundongos , Modelos Animais
13.
Br J Anaesth ; 123(4): 497-505, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399212

RESUMO

BACKGROUND: Orexin can facilitate emergence after general anaesthesia via multiple neural pathways. Dopaminergic neurones in the ventral tegmental area (VTA) participate in behavioural arousal from anaesthesia. We investigated the regulation of dopaminergic VTA neurones by orexinergic neurones during emergence from general anaesthesia. METHODS: Orexins were microinjected into the VTA to determine the effects on isoflurane anaesthesia induction, emergence, and maintenance. Orexin receptors and dopaminergic neurones in the VTA were identified using immunofluorescence. Orexinergic terminals in the VTA were optogenetically regulated to detect the endogenous orexin-mediated regulation of dopaminergic neurones during anaesthesia in Hcrtcre rats. RESULTS: Injection of orexin-A (100 pmol) into the VTA reduced emergence time [from 949 (118) to 727 (101) s; P=0.0058] and reduced the electroencephalographic burst-suppression ratio (BSR) (26.6 [10.2]% vs 44.3 [6.8]%; P=0.0027) during isoflurane anaesthesia. The percentage of dopaminergic neurones that expressed either orexin-1 receptor or orexin-2 receptor was 73.4 (5.0)% and 74.4 (62.4)%, respectively. Optogenetic activation of orexinergic projections to the VTA reduced the BSR (from 40.5 [2.7]% to 22.4 [11.8]%; P=0.0019) and facilitated emergence (915 [89] vs 685 [68] s; P=0.0026), whereas optical inhibition prolonged the time to wakefulness (from 941 [92] to 1279 [250] s; P=0.011). Dopaminergic neurones in the VTA showed increased firing frequency (387 [78]% of control, P=0.005) after bath application of orexin-A. CONCLUSIONS: Orexin promotes emergence from isoflurane anaesthesia through activation of dopaminergic neurones in the VTA.


Assuntos
Anestésicos Inalatórios/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Isoflurano/farmacologia , Orexinas/administração & dosagem , Área Tegmentar Ventral/efeitos dos fármacos , Período de Recuperação da Anestesia , Animais , Masculino , Modelos Animais , Ratos
14.
Int J Exp Pathol ; 100(3): 153-160, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31321834

RESUMO

Animal models are widely used to study the physiopathology of human diseases. However, the influence of gender on modern society diet style-induced cardiovascular disease has not thus far been explored in these models. Thus, this study investigated cardiovascular remodelling in C57BL/6J mice fed a diet rich in saturated fat, sucrose and salt, evaluating gender effect on this process. Male and female C57BL/6J mice were fed AIN93M diet or a modified AIN93M rich in fat, sucrose and salt (HFSS) for 12 weeks. Body mass, water and food intake and cardiovascular remodelling were assessed. The HFSS diet did not lead to body mass gain or glucose metabolism disturbance as assessed by serum glucose, insulin and oral glucose tolerance test. However, female mice on a HFSS diet had increased visceral and subcutaneous adiposity. Only male mice displayed heart hypertrophy. The left ventricle was not hypertrophied in either male or female mice, but its lumen was dilated. Intramyocardial arteries and the thoracic aorta showed media thickening in male mice, but in the female it was only observed in the thoracic aorta. Finally, intramyocardial artery dilation was present in both genders, but not in the aorta. Therefore changes in LV dimensions and arterial remodelling were influenced by both gender and the HFSS diet. In conclusion, male and female C57BL/6J mice suffered cardiovascular remodelling after 12 weeks of HFSS feeding, although they did not develop obesity or diabetes. Sexual dimorphism occurred in response to diet for body adiposity, heart hypertrophy and intramyocardial artery remodelling.


Assuntos
Dieta Hiperlipídica , Obesidade/metabolismo , Sacarose/metabolismo , Animais , Gorduras na Dieta/farmacologia , Camundongos Endogâmicos C57BL , Modelos Animais , Caracteres Sexuais
15.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(7): 697-700, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31302973

RESUMO

Endoscopic submucosal dissection (ESD) is the gold standard technique for performing en bloc resection of large superficial tumors in the upper and lower gastrointestinal tract. It has not started in China until early 2006, when it was introduced at Endoscopy Center of Zhongshan Hospital. However, ESD is technically more difficult and can result in more complications, limiting its development in China. At present, reports about ESD training system in China are still not available. Therefore, our center continuously explored and gradually established structured training courses relied on the live pig model. Between 2009 and 2013, we held 23 hands-on ESD training workshops with 550 endoscopists. Questionnaires were distributed via e-mail, and there were 460 participants performing ESD in a step-up approach on the live pigs. More than one half of trainees could perform ESD with en bloc resection in the imaginary "lesion" of colon and stomach, and there were higher rates of hemorrhage and perforation occurring in colorectal ESD as compared to gastric ESD. After graduating from our hands-on workshop, up to over 90% of participants started ESD practice in their home hospitals. It was mostly provided by high-grade hospitals (IIIA) which played a major role as tertiary referral centers, covering almost all provinces and major cities in China. The training on live pig model revealed to be safe and effective as a prior step to its application in humans. It may enable novice endoscopists to acquire ESD skills and start performing ESD as soon as possible. The role of adequate training is of course to influence the spread of this technique and promote ESD development around China.


Assuntos
Colo/cirurgia , Ressecção Endoscópica de Mucosa/educação , Estômago/cirurgia , Animais , China , Educação , Ressecção Endoscópica de Mucosa/métodos , Humanos , Modelos Animais , Suínos
16.
J Agric Food Chem ; 67(28): 8007-8019, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31268702

RESUMO

Cow and human milk have been reported to contain dioxins ranging from 0.023 to 26.46 and 0.88 to 19 pg/g of fat, respectively. However, the toxic effects of the dioxins in the milk in this range of concentrations were not explored. Therefore, considering the outbred livestock tissues as better models than inbred laboratory animals, the present study targeted to study the effect of dioxins present in the milk on three-dimensionally (3D) cultured buffalo primary hepatocyte spheroids. The spheroids were treated with a model dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), directly and also through milk fat at different concentrations (i.e, 0.02-20 pg/mL) for 24 h. Among the liver-cell-specific (ALB, HNF4α, and AFP) genes, a similar ALB and upregulated HNF4α expression at all treatments indicated the functional and transcriptionally active hepatocyte spheroids. Supportingly, no significant difference in the antiapoptotic gene expression between the treatments of milk fat and milk fat containing dioxins indicated the survivability of the spheroids during dioxin treatments. Among the selected TCDD responsive (CYP1A1, CYP1A2, AHR, CYP1B1, and TIPARP) genes, a nonsignificant increasing trend of the CYP1A1 expression was observed from 0.2 to 10 pg/mL of TCDD concentration through milk fat. This pattern was similar to the reported insensitive response of human primary hepatocytes toward dioxins than that of rat primary hepatocytes. This may indicate that the buffalo hepatocyte spheroids could be better models than rats for TCDD hepatotoxic studies. Further, TCDD in the milk in the range of 0.02-20 pg/mL concentration may not be very hepatotoxic.


Assuntos
Dioxinas/farmacologia , Hepatócitos/efeitos dos fármacos , Leite/química , Animais , Búfalos , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Dioxinas/análise , Contaminação de Alimentos/análise , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Animais , Ratos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo
18.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
19.
Am J Orthod Dentofacial Orthop ; 156(1): 75-86, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256844

RESUMO

INTRODUCTION: Maintaining tooth anchorage during orthodontic treatment has challenged orthodontists and threatening the success of some orthodontic therapy. The objective of this study was to evaluate the effect of local administration of simvastatin on orthodontic tooth movement. METHODS: Nickel-titanium coil springs were used to induce orthodontic tooth movement in 10 white New Zealand rabbits for 21 days. A split-mouth design was implemented where one mandibular quadrant received local administration of simvastatin and the corresponding mandibular quadrant received control vehicle solution on a weekly basis. Magnitudes of tooth movement were measured on 3-dimensional models of the experimental teeth. Animals were killed at the end of the experimental period to allow histomorphometric analysis of alveolar bone modeling. RESULTS: The total magnitude of tooth movement in the quadrant receiving simvastatin was significantly less than that in the quadrant receiving control vehicle solution. Local administration of simvastatin resulted in a significant percentage of inhibition of tooth movement of 39.8 ± 22.6%. Histomorphometric analysis revealed a significant reduction in the numbers of osteoclasts and areas of active bone-resorptive lacunae hindering bone resorption processes in the quadrant receiving simvastatin. CONCLUSIONS: Local administration of simvastatin can reduce the rate and magnitude of orthodontic tooth movement. Moreover, local administration of simvastatin diminishes bone resorption processes associated with orthodontic tooth movement reducing the number of osteoclasts and the subsequent area of active bone resorption.


Assuntos
Reabsorção Óssea/patologia , Osteoclastos/efeitos dos fármacos , Sinvastatina/administração & dosagem , Sinvastatina/antagonistas & inibidores , Técnicas de Movimentação Dentária/métodos , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/patologia , Animais , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/diagnóstico por imagem , Masculino , Mandíbula/irrigação sanguínea , Mandíbula/efeitos dos fármacos , Mandíbula/patologia , Modelos Animais , Níquel/química , Aparelhos Ortodônticos , Fios Ortodônticos , Osteoclastos/patologia , Coelhos , Titânio/química , Técnicas de Movimentação Dentária/instrumentação
20.
Chem Commun (Camb) ; 55(64): 9463-9466, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31328200

RESUMO

A novel hydrosoluble near-infrared (NIR) fluorescent probe that could specifically identify tyrosinase has been successfully constructed and applied for imaging of tyrosinase in living cells and zebrafish. Notably, the probe has been successfully applied to the diagnosis of melanoma in a xenogeneic mouse model.


Assuntos
Corantes Fluorescentes/química , Monofenol Mono-Oxigenase/análise , Animais , Hidrólise , Melanoma Experimental/diagnóstico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Solubilidade
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