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1.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445367

RESUMO

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)-an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO-control, AIA-untreated adjuvant-induced arthritis, AIA-BIL-adjuvant-induced arthritis administrated UCB, CO-BIL-control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund's adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Bilirrubina/administração & dosagem , Adjuvante de Freund/efeitos adversos , Lipídeos/efeitos adversos , Mycobacterium/imunologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Bilirrubina/farmacologia , Proteína C-Reativa , Ceruloplasmina/metabolismo , Injeções Intraperitoneais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Resultado do Tratamento
2.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445376

RESUMO

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.


Assuntos
Ketamina/administração & dosagem , Fenóis/administração & dosagem , Piperidinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Animais , Injeções Intraperitoneais , Ketamina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
3.
Toxicol Lett ; 350: 283-291, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371142

RESUMO

Diethylenetriaminepentaacetate (DTPA) is the most widely used chelating agent for Pu and Am. Volunteers were assigned to receive intravenous injections or aerosol inhalations of 1 g of DTPA on days 1-4; volunteers received once daily injections of CaDTPA or ZnDTPA, CaDTPA inhalation as an aerosol, or CaDTPA injection on day 1 and ZnDTPA on days 2-4. CaDTPA injection or inhalation increased the excretion rates of Zn in urine with concomitantly reduced levels of serum Zn. Injection of CaDTPA reduced activities of serum alkaline phosphatase (AP) in parallel with the kinetics of Zn, whereas CaDTPA and ZnDTPA injection reduced activities of lactate dehydrogenase (LDH), and reduced activities of creatinine kinase (CK) were observed upon CaDTPA injection and its inhalation. Intravenous administration of CaDTPA and ZnDTPA enhanced excretion rates of Mn in urine, whereas transient reduction of Mn levels in serum was detected only via CaDTPA injection. Both CaDTPA and ZnDTPA transiently reduced levels of Mg in serum without affecting the excretion rates. On the other hand, both DTPAs increased excretion rates of toxic metals such as Pb and Cd, and CaDTPA also increased the rates of Hg. These results suggest that DTPA, and especially CaDTPA, removes essential metals and that the activities of these metalloenzymes are good indicators for the imbalance of essential metals during the DTPA administration. Our results also show that CaDTPA injection is more potent for removing these metals than ZnDTPA and inhalation of CaDTPA, and DTPA may be useful for the treatment of acute heavy metal poisoning with Pb, Cd, or Hg.


Assuntos
Quelantes/análise , Quelantes/farmacologia , Ácido Pentético/análise , Ácido Pentético/farmacocinética , Zinco/sangue , Zinco/urina , Administração por Inalação , Adulto , Aerossóis , Voluntários Saudáveis , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Japão , Masculino , Adulto Jovem
4.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209507

RESUMO

CLPB (Caseinolytic peptidase B) protein is a conformational mimetic of α-MSH, an anorectic hormone. Previous in vivo studies have already shown the potential effect of CLPB protein on food intake and on the production of peptide YY (PYY) by injection of E. coli wild type (WT) or E. coli ΔClpB. However, until now, no study has shown its direct effect on food intake. Furthermore, this protein can fragment naturally. Therefore, the aim of this study was (i) to evaluate the in vitro effects of CLPB fragments on PYY production; and (ii) to test the in vivo effects of a CLPB fragment sharing molecular mimicry with α-MSH (CLPB25) compared to natural fragments of the CLPB protein (CLPB96). To do that, a primary culture of intestinal mucosal cells from male Sprague-Dawley rats was incubated with proteins extracted from E. coli WT and ΔCLPB after fragmentation with trypsin or after a heat treatment of the CLPB protein. PYY secretion was measured by ELISA. CLPB fragments were analyzed by Western Blot using anti-α-MSH antibodies. In vivo effects of the CLPB protein on food intake were evaluated by intraperitoneal injections in male C57Bl/6 and ob/ob mice using the BioDAQ® system. The natural CLPB96 fragmentation increased PYY production in vitro and significantly decreased cumulative food intake from 2 h in C57Bl/6 and ob/ob mice on the contrary to CLPB25. Therefore, the anorexigenic effect of CLPB is likely the consequence of enhanced PYY secretion.


Assuntos
Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Endopeptidase Clp/farmacologia , Proteínas de Escherichia coli/farmacologia , Proteínas de Choque Térmico/farmacologia , Peptídeo YY/metabolismo , Animais , Anticorpos Antibacterianos/metabolismo , Western Blotting , Técnicas de Cultura de Células , Fragmentação do DNA , Ensaio de Imunoadsorção Enzimática , Escherichia coli/química , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201550

RESUMO

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.


Assuntos
Encéfalo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Metotrexato/toxicidade , Bainha de Mielina/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Bainha de Mielina/patologia , Síndromes Neurotóxicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/genética
6.
Fish Physiol Biochem ; 47(4): 1299-1311, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241762

RESUMO

Genistein is an abundant phytoestrogen in soybean. This study aimed to determine the effects of genistein on cholesterol distribution and metabolism in female yellow catfish. Three hundred fish (49.2 ± 1.4 g) were randomly divided into five treatments and received intraperitoneal injections as follows: (1) blank, no injection; (2) control, vehicle only; (3) E2, 17ß-estradiol at 10 µg·g-1 body weight; (4) low genistein doses, genistein at 10 µg·g-1 body weight; (5) high genistein doses, genistein at 100 µg·g-1 body weight. Both high and low genistein doses significantly reduced (p < 0.05) serum TC and LDL-C 24 h after injection. Moreover, the high genistein doses significantly reduced (p < 0.05) serum HDL-C. Both high and low doses of genistein significantly increased (p < 0.05) hepatic TC. Only high genistein doses significantly increased (p < 0.05) ovary TC. In the liver, both high and low genistein doses significantly increased (p < 0.05) protein and mRNA expression of ldlr. Meanwhile, high genistein doses significantly decreased (p < 0.05) mRNA expression of hmgcr. In ovary tissue, high genistein doses significantly decreased (p < 0.05) mRNA expression of cyp11a1. These results suggested that genistein affected the cholesterol distribution in female yellow catfish. Both high and low doses of genistein reduced cholesterol content in blood and increased its content in the liver by increasing the uptake of blood cholesterol. Meanwhile, high genistein doses may inhibit hepatic cholesterol synthesis. Additionally, high genistein doses could increase cholesterol transfer from serum into the ovary and disturb cholesterol conversion to pregnenolone.


Assuntos
Peixes-Gato/metabolismo , Colesterol/metabolismo , Genisteína/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Peixes-Gato/sangue , Peixes-Gato/genética , Colesterol/sangue , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Fosfoproteínas/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
7.
J Vet Med Sci ; 83(8): 1173-1177, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34121040

RESUMO

Genital bacterial infection is one of the most important causes of infertility, however, bacteria frequently exist in seminal fluid. Sperm express Toll-like receptors (TLRs) on their cell surfaces and bacterial recognition by TLRs induces sperm apoptosis. In this study, we examined the lactoferrin (LF) potentiality on sperm apoptosis induced by bacterial lipopolysaccharide (LPS). The TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay indicated that TUNEL-positive sperm cells were scarce in the group treated with LF and LPS (LF/LPS group) compared to the group treated with LPS only (LPS group). In addition, real-time RT-PCR detected lower mRNA expression levels of apoptosis-associated genes in the LF/LPS group compared to the LPS group. These results indicate that LF treatment of semen might decrease LPS-induced apoptosis of sperm.


Assuntos
Lactoferrina , Lipopolissacarídeos , Animais , Apoptose , Injeções Intraperitoneais/veterinária , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Espermatozoides
8.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066508

RESUMO

Ovarian cancer (OC) metastases frequently occur through peritoneal dissemination, and they contribute to difficulties in treatment. While photodynamic therapy (PDT) has the potential to treat OC, its use is often limited by tissue penetration depth and tumor selectivity. Herein, we combined Cerenkov radiation (CR) emitted by 18F-FDG accumulated in tumors as an internal light source and several photosensitizer (PS) candidates with matched absorption bands, including Verteporfin (VP), Chlorin e6 (Ce6) and 5'-Aminolevulinic acid (5'-ALA), to evaluate the anti-tumor efficacy. The in vitro effect of CR-induced PDT (CR-PDT) was evaluated using a cell viability assay, and the efficiency of PS was assessed by measuring the singlet oxygen production. An intraperitoneal ES2 OC mouse model was used for in vivo evaluation of CR-PDT. Positron emission tomography (PET) imaging and bioluminescence-based imaging were performed to monitor the biologic uptake of 18F-FDG and the therapeutic effect. The in vitro studies demonstrated Ce6 and VP to be more effective PSs for CR-PDT. Moreover, VP was more efficient in the generation of singlet oxygen and continued for a long time when exposed to fluoro-18 (18F). Combining CR emitted by 18F-FDG and VP treatment not only significantly suppressed tumor growth, but also prolonged median survival times compared to either monotherapy.


Assuntos
Fluordesoxiglucose F18/uso terapêutico , Neoplasias Ovarianas/terapia , Fotoquimioterapia , Radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Feminino , Injeções Intraperitoneais , Camundongos Endogâmicos BALB C
9.
J Med Microbiol ; 70(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34115583

RESUMO

Introduction. Leishmaniasis is a neglected tropical and subtropical disease caused by over 20 protozoan species.Hypothesis. Treatment of this complex disease with traditional synthetic drugs is a major challenge worldwide. Natural constituents are unique candidates for future therapeutic development.Aim. This study aimed to assess the in vivo anti-leishmanial effect of the Gossypium hirsutum extract, and its fractions compared to the standard drug (Glucantime, MA) in a murine model and explore the mechanism of action.Methodology. Footpads of BALB/c mice were infected with stationary phase promastigotes and treated topically and intraperitoneally with G. hirsutum extract, its fractions, or Glucantime, 4 weeks post-infection. The extract and fractions were prepared using the Soxhlet apparatus with chloroform followed by the column procedure.Results. The crude extract significantly decreased the footpad parasite load and lesion size compared to the untreated control group (P<0.05), as revealed by dilution assay, quantitative real-time PCR, and histopathological analyses. The primary mode of action involved an immunomodulatory role towards the Th1 response in the up-regulation of IFN-γ and IL-12 and the suppression of IL-10 gene expression profiling against cutaneous leishmaniasis caused by Leishmania major.Conclusion. This finding suggests that the extract possesses multiple combinatory effects of diverse bioactive phytochemical compositions that exert its mechanisms of action through agonistic-synergistic interactions. The topical extract formulation could be a suitable and unique candidate for future investigation and pharmacological development. Further studies are crucial to evaluate the therapeutic potentials of the extract alone and in combination with conventional drugs using clinical settings.


Assuntos
Antiprotozoários/uso terapêutico , Gossypium , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Administração Tópica , Animais , Antiprotozoários/farmacologia , Feminino , Injeções Intraperitoneais , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/genética , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/metabolismo , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/fisiopatologia , Linfonodos/patologia , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Baço/parasitologia , Baço/patologia , Células Th1/imunologia , Transcriptoma
12.
Aging (Albany NY) ; 13(12): 16656-16666, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34170847

RESUMO

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.


Assuntos
Neointima/metabolismo , Neointima/patologia , Receptor de Morte Celular Programada 1/metabolismo , Veias/metabolismo , Veias/patologia , Animais , Humanos , Hiperplasia/metabolismo , Injeções Intraperitoneais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Água
13.
Toxins (Basel) ; 13(5)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063025

RESUMO

Understanding the toxicity and production rates of the various secondary metabolites produced by Gambierdiscus and cohabitating benthic dinoflagellates is essential to unravelling the complexities associated with ciguatera poisoning. In the present study, a sulphated cyclic polyether, gambierone, was purified from Gambierdiscus cheloniae CAWD232 and its acute toxicity was determined using intraperitoneal injection into mice. It was shown to be of low toxicity with an LD50 of 2.4 mg/kg, 9600 times less toxic than the commonly implicated Pacific ciguatoxin-1B, indicating it is unlikely to play a role in ciguatera poisoning. In addition, the production of gambierone and 44-methylgambierone was assessed from 20 isolates of ten Gambierdiscus, two Coolia and two Fukuyoa species using quantitative liquid chromatography-tandem mass spectrometry. Gambierone was produced by seven Gambierdiscus species, ranging from 1 to 87 pg/cell, and one species from each of the genera Coolia and Fukuyoa, ranging from 2 to 17 pg/cell. The production of 44-methylgambierone ranged from 5 to 270 pg/cell and was ubiquitous to all Gambierdiscus species tested, as well as both species of Coolia and Fukuyoa. The relative production ratio of these two secondary metabolites revealed that only two species produced more gambierone, G. carpenteri CAWD237 and G. cheloniae CAWD232. This represents the first report of gambierone acute toxicity and production by these cohabitating benthic dinoflagellate species. While these results demonstrate that gambierones are unlikely to pose a risk to human health, further research is required to understand if they bioaccumulate in the marine food web.


Assuntos
Ciguatoxinas/toxicidade , Dinoflagelados/metabolismo , Éteres/toxicidade , Animais , Cromatografia Líquida , Éteres/administração & dosagem , Éteres/isolamento & purificação , Feminino , Injeções Intraperitoneais , Dose Letal Mediana , Camundongos , Metabolismo Secundário , Espectrometria de Massas em Tandem , Testes de Toxicidade Aguda
14.
Biomed Pharmacother ; 140: 111725, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34015580

RESUMO

BACKGROUND: Pain after laparoscopic cholecystectomy remains a major challenge. Ondansetron blocks sodium channels and may have local anesthetic properties. AIMS: To investigate the effect of intraperitoneal administration of ondansetron for postoperative pain management as an adjuvant to intravenous acetaminophen in patients undergoing laparoscopic cholecystectomy. METHODS: Patients scheduled for elective laparoscopic cholecystectomy were randomized into two groups (n = 25 each) to receive either intraperitoneal ondansetron or saline injected in the gall bladder bed at the end of the procedure. The primary outcome was the difference in pain from baseline to 24-h post-operative assessed by comparing the area under the curve of visual analog score between the two groups. RESULTS: The derived area under response curve of visual analog scores in the ondansetron group (735.8 ± 418.3) was 33.97% lower than (p = 0.005) that calculated for the control group (1114.4 ± 423.9). The need for rescue analgesia was significantly lower in the ondansetron (16%) versus in the control group (54.17%) (p = 0.005), indicating better pain control. The correlation between the time for unassisted mobilization and the area under response curve of visual analog scores signified the positive analgesic influence of ondansetron (rs =0.315, p = 0.028). The frequency of nausea and vomiting was significantly lower in patients who received ondansetron than that reported in the control group (p = 0.023 (8 h), and 0.016 (24 h) respectively). CONCLUSIONS: The added positive impact of ondansetron on postoperative pain control alongside its anti-emetic effect made it a unique novel option for patients undergoing laparoscopic cholecystectomy.


Assuntos
Acetaminofen/uso terapêutico , Adjuvantes Farmacêuticos/uso terapêutico , Analgésicos/uso terapêutico , Antieméticos/uso terapêutico , Colecistectomia Laparoscópica , Ondansetron/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Injeções Intraperitoneais , Masculino , Pessoa de Meia-Idade , Náusea e Vômito Pós-Operatórios/tratamento farmacológico
15.
Toxicol Sci ; 182(1): 10-28, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-33944952

RESUMO

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10-5, 5 × 10-3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK.


Assuntos
Nitrosaminas , Espectrometria de Massas em Tandem , Animais , Carcinógenos , Cromatografia Líquida de Alta Pressão , Dano ao DNA , Exposição por Inalação , Injeções Intraperitoneais , Masculino , Nitrosaminas/toxicidade , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Toxicocinética
16.
Br J Anaesth ; 127(3): 435-446, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33972091

RESUMO

BACKGROUND: We recently showed that a neurosteroid analogue, (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile (3ß-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3ß-OH further using electroencephalography. METHODS: We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3ß-OH (30 and 60 mg kg-1) administered intraperitoneally or intravenously to young adult male and female rats. RESULTS: We found dose-dependent sex differences in 3ß-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3ß-OH 30 mg kg-1. However, at the higher dose (60 mg kg-1, i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2-6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg-1 i.v., female rats appeared more sensitive to 3ß-OH with relatively small changes within delta (1-4 Hz) and alpha (8-13 Hz) bands. Finally, 3ß-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg-1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. CONCLUSIONS: Based on its behavioural effects and EEG signature, 3ß-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats.


Assuntos
Androstanóis/farmacologia , Ondas Encefálicas/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Eletrocorticografia , Resposta de Imobilidade Tônica/efeitos dos fármacos , Neuroesteroides/farmacologia , Nitrilas/farmacologia , Androstanóis/administração & dosagem , Animais , Córtex Cerebral/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Neuroesteroides/administração & dosagem , Nitrilas/administração & dosagem , Ratos Sprague-Dawley , Fatores Sexuais , Fatores de Tempo
17.
J Toxicol Sci ; 46(5): 223-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952799

RESUMO

Sodium carboxy methyl cellulose (SCMC) is an important absorbable biomaterial for anti-adhesion and hemostasis medical devices used in the abdominal cavity. However, the systemic toxicity of SCMC following intraperitoneal route has not been revealed sufficiently. Three SCMC solutions with gradient concentrations were intraperitoneally injected into 3 groups of rats with the doses of 50 mg/kg, 320 mg/kg and 2000 mg/kg respectively all at once to observe the dose-dependence of systemic reactions of SCMC and 10 rats (5 rats per sex) of each group were sacrificed 3 days, 7 days, 28 days and 90 days after injection to evaluate the time-dependence of the reactions. A range of adverse effects were shown in rats of the high-dose group which were found varied with time extending and virtually disappeared 90 days after injection. Slight reactions were observed in the medium-dose group while negligible effects were found in the low-dose group. The intraperitoneal application of SCMC can induce reversible systemic adverse effects to rats at the dose higher than 320 mg/kg and it is essential to take both dose- and time-dependent effects into account while designing a systemic toxicity study for absorbable biomaterials.


Assuntos
Carboximetilcelulose Sódica/toxicidade , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia , Útero/efeitos dos fármacos , Útero/patologia
18.
Methods Mol Biol ; 2321: 43-51, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34048006

RESUMO

Mouse models of bacterial sepsis are widely used in research to investigate the underlying molecular mechanisms of sepsis and to develop clinically useful therapeutic regimens. Three commonly used mouse sepsis models include (a) injection of bacterial endotoxin, (b) infusion of cultured bacteria, and (c) cecal ligation and puncture. Here we describe the induction of bacterial sepsis in mice by intraperitoneal injection of cultured live Escherichia coli cells. The severity of the sepsis can be regulated by the number of E. coli cells injected into the peritoneal cavity of mice.


Assuntos
Escherichia coli/crescimento & desenvolvimento , Sepse/microbiologia , Animais , Ceco/microbiologia , Modelos Animais de Doenças , Endotoxinas/administração & dosagem , Injeções Intraperitoneais/métodos , Ligadura/métodos , Camundongos , Camundongos Endogâmicos C57BL , Cavidade Peritoneal/microbiologia , Punções/métodos
19.
Aging (Albany NY) ; 13(9): 12800-12816, 2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934089

RESUMO

Intracranial aneurysms (IAs) are common cerebrovascular diseases that carry a high mortality rate, and the mechanisms that contribute to IA formation and rupture have not been elucidated. ADAMTS-5 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 5) is a secreted proteinase involved in matrix degradation and ECM (extracellular matrix) remodeling processes, and we hypothesized that the dysregulation of ADAMTS-5 could play a role in the pathophysiology of IA. Immunofluorescence revealed that the ADAMTS-5 levels were decreased in human and murine IA samples. The administration of recombinant protein ADAMTS-5 significantly reduced the incidence of aneurysm rupture in the experimental model of IA. IA artery tissue was collected and utilized for histology, immunostaining, and specific gene expression analysis. Additionally, the IA arteries in ADAMTS-5-administered mice showed reduced elastic fiber destruction, proteoglycan accumulation, macrophage infiltration, inflammatory response, and apoptosis. To further verify the role of ADAMTS-5 in cerebral vessels, a specific ADAMTS-5 inhibitor was used on another model animal, zebrafish, and intracranial hemorrhage was observed in zebrafish embryos. In conclusion, our findings indicate that ADAMTS-5 is downregulated in human IA, and compensatory ADAMTS-5 administration inhibits IA development and rupture with potentially important implications for treating this cerebrovascular disease.


Assuntos
Proteína ADAMTS5/metabolismo , Matriz Extracelular/patologia , Aneurisma Intracraniano/complicações , Proteína ADAMTS5/administração & dosagem , Proteína ADAMTS5/genética , Adulto , Idoso , Animais , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Humanos , Injeções Intraperitoneais , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/patologia , Aneurisma Intracraniano/cirurgia , Masculino , Camundongos , Proteólise , Proteínas Recombinantes/administração & dosagem , Ruptura Espontânea/etiologia , Ruptura Espontânea/patologia , Ruptura Espontânea/prevenção & controle , Remodelação Vascular , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismo
20.
Aging (Albany NY) ; 13(8): 12160-12178, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33901014

RESUMO

We previously reported the neuroprotective effects of (+)-balasubramide derived compound 3C, but its action on atherosclerosis in vivo remains unknown. The study was designed to investigate the potential effects of 3C on atherogenesis and explore the possible underlying mechanisms. 3C ameliorated high-fat diet-induced body weight gain, hyperlipidemia, and atherosclerotic plaque burden in apolipoprotein E-deficient (ApoE-/-) mice after 10 weeks of treatment. 3C suppressed the expression of genes involved in triglyceride synthesis in liver. 3C prevented aortic inflammation as evidenced by reduction of adhesive molecule levels and macrophage infiltration. Mechanistic studies revealed that activation of AMP-activated protein kinase (AMPK) is central to the athero-protective effects of 3C. Increased AMPK activity by 3C resulted in suppressing interferon-γ (IFN-γ) induced activation of signal transducer and activator of transcription-1 (STAT1) and stimulator of interferon genes (STING) signaling pathways and downstream pro-inflammatory markers. Moreover, 3C inhibited ox-LDL triggered lipid accumulation and IFN-γ induced phenotypic switch toward M1 macrophage in RAW 264.7 cells. Our present data suggest that 3C prevents atherosclerosis via pleiotropic effects, including amelioration of lipid profiles, vascular inflammation and macrophage pro-inflammatory phenotype. 3C has the potential to be developed as a promising drug for atherosclerosis and related cardiovascular disease.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções Intraperitoneais , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout para ApoE , Células RAW 264.7 , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos
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