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1.
J Appl Toxicol ; 40(7): 965-978, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32084673

RESUMO

An ethanol extract complex of Descurainia sophia seeds and Peucedanum praeruptorum roots, called BP10A, has antitumor potential against colorectal cancer. In the present study, we evaluated the 28-day oral toxicity and the genotoxicity of BP10A. The subacute toxicity test was done through oral administration to mice. ICR mice (n = 10) received daily oral BP10A doses of 0, 500, 1000 and 2000 mg/kg for 28 consecutive days. During administration, general clinical signs, food consumption, organ weights, and hematologic, biochemical and histopathological parameters in male and female mice were assessed. No significant adverse effects up to the highest dose (2000 mg/kg) were found. The genotoxicity was evaluated using a battery of tests, including an in vitro bacterial reverse mutation (Ames) test, an in vivo micronucleus test using bone marrow cells in ICR mice and a chromosomal aberration test using CHL/IU cells. BP10A did not show any genotoxic signs in the Ames (up to 5000 µg/plate), micronucleus (up to 5000 mg/kg) and the chromosomal aberration tests (550-1750 µg/mL). Therefore, BP10A was considered safe based on the subacute toxicity and genotoxicity results, indicating that it is a useful pharmaceutical material with no adverse toxicity.

2.
J Ethnopharmacol ; 249: 112381, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31715286

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythia viridissima fruit, one of Forsythiae Fructus (FF) is widely used in traditional medicine to treat diverse diseases-related clinical symptoms, including fever, pain, vomiting, nausea, and abscess. However, the safety of FF has not been fully assessed. AIM OF THE STUDY: In this study, we evaluated the acute oral toxicity and genotoxic potential of an aqueous extract of Forsythia viridissima fruits (EFVF). MATERIALS AND METHODS: For an acute oral toxicity test, male and female SD rats (n = 5) orally received a single dose of 5000 mg/kg EFVF. The genotoxic potential of EFVF was evaluated with a battery of tests, including an in vitro bacterial reverse mutation test using five mutant strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), an in vitro chromosomal aberration test using Chinese hamster lung (CHL/IU) cells, and an in vivo micronucleus test using bone marrow cells in male ICR mice that were orally administered EFVF. All tests were completed in compliance with Organization for Economic Cooperation and Development guidelines and/or regional regulatory standards for toxicity tests. RESULTS: In the acute oral toxicity test, the animals did not show any significant mortality and body weight changes for 14 days following a single dose of EFVF at 5000 mg/kg. There was no evidence of genotoxicity of EFVF based on the results of the in vitro bacterial reverse mutation test (up to 5000 µg/plate), the in vivo micronucleus test (up to 5000 mg/kg), and the in vitro chromosomal aberration test (1100-2500 µg/mL). CONCLUSIONS: We found that EFVF is safe with regard to acute toxicity in rats as well as genotoxicity such as mutagenesis or clastogenesis under the present experimental conditions. These results might support the safety of EFVF as a potential therapeutic material for the traditional use or pharmaceutical development.

3.
BMC Complement Altern Med ; 19(1): 339, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783843

RESUMO

BACKGROUND: The dried fruits of Forsythia suspensa has generally been used to clear heat and detoxify in traditional Korean and Chinese medicine. Oxaliplatin is a first-line treatment chemotherapeutic agent for advanced colorectal cancer, but it induces peripheral neuropathy as an adverse side effect affecting the treatment regimen and the patient's quality of life. The present study was conducted to evaluate the neuroprotective effects of an aqueous extract of F. suspensa fruits (EFSF) on oxaliplatin-induced peripheral neuropathy. METHODS: The chemical components from EFSF were characterized and quantified using the ultra-high performance liquid chromatography-diode array detector system. The cytotoxicities of anticancer drugs in cancer cells and PC12 cells were assessed by the Ez-Cytox viability assay. To measure the in vitro neurotoxicity, the neurite outgrowth was analyzed in the primary dorsal root ganglion (DRG) cells, and neural PC12 cells that were differentiated with nerve growth factor. To evaluate the in vivo neuroprotective activity, the von Frey test was performed in six-week-old male mice (C57BL/6) receiving EFSF (60-600 mg/kg) in the presence of 20-30 mg/kg cumulative doses of oxaliplatin. Thereafter, the mice were euthanized for immunohistochemical staining analysis with an antibody against PGP9.5. RESULTS: EFSF attenuated the cytotoxic activities of the various anticancer drugs in neural PC12 cells, but did not affect the anticancer activity of oxaliplatin in human cancer cells. Oxaliplatin remarkably induced neurotoxicities including cytotoxicity and the inhibited neurite outgrowth of DRG and neural PC12 cells. However, the co-treatment of EFSF (100 µg/ml) with oxaliplatin completely reversed the oxaliplatin-induced neurotoxicity. Forsythoside A, the major component of EFSF, also exerted remarkable neuroprotective effects against the oxaliplatin-induced neurotoxicity. In addition, EFSF (60-200 mg/kg) significantly alleviated the oxaliplatin-induced mechanical allodynia and loss of intra-epidermal nerve fiber to the levels of the vehicle control in the mouse peripheral neuropathy model. CONCLUSIONS: EFSF could be considered a useful herbal medicine for the treatment of peripheral neuropathy in cancer patients receiving chemotherapy with oxaliplatin.


Assuntos
Forsythia , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/toxicidade , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuritos/efeitos dos fármacos , Neurotoxinas/toxicidade , Células PC12 , Ratos
4.
Comb Chem High Throughput Screen ; 22(5): 326-332, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31446890

RESUMO

BACKGROUND: Traditionally, Phragmitis rhizoma has been prescribed to relive a fever, vomiting, dysuria, and constipation, and to promote secretion of fluids. In addition, recent studies have reported its efficacy as a diuretic and antiemetic. Our previous study demonstrated that the Phragmitis rhizoma aqueous extract (EPR) ameliorates docetaxel (DTX)-induced myelotoxicity. AIM AND OBJECTIVE: This study was aimed to investigate the effects of EPR on the pharmacokinetics of DTX in Sprague-Dawley rats. MATERIALS AND METHODS: The animals received an intravenous injection of DTX (5 mg/kg) with or without oral EPR (100 mg/kg) pretreatment for 1 or 6 days. The pharmacokinetics of plasma DTX was analyzed using an ultra-performance liquid chromatography-tandem mass spectrometry system, and pharmacokinetic parameters were estimated via noncompartmental analysis. RESULTS: Relative to the control group (DTX alone), EPR pretreatment did not affect significantly the overall profiles of plasma DTX levels. Consecutively pretreated EPR for 6 days slightly altered AUC0-t and Cmax of DTX by 122 and 145.9%, respectively, but these data did not reach the threshold of statistical significance (p > 0.05). CONCLUSION: These results indicate that DTX exposure may not be affected by EPR treatment at the dose level used in this study, suggesting that oral EPR can be used safely when taken with intravenously injected DTX. However, further studies under the stringent conditions are needed when chronic treatment of EPR and anticancer drug.

5.
J Ethnopharmacol ; 241: 112025, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31189082

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: A rhizome of Phragmites communis Trinius has been used in traditional medicine to remove a heat, relieve vomiting and fever, nourish body fluids, and treat diseases like cancers. However, the safety of Phragmitis rhizoma has not yet been fully assessed. AIM OF THE STUDY: The present study evaluated the genotoxicity of an aqueous extract of Phragmitis rhizoma (AEPR). MATERIALS AND METHODS: The genotoxic potential of AEPR was evaluated using both in vitro and in vivo assay systems: a bacterial reverse mutation (AMES) test using auxotrophic mutant strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), a chromosomal aberration test using Chinese hamster lung cells, and a micronucleus test using bone marrow cells from male ICR mice subjected to an oral administration of AEPR. All tests were completed in compliance with the OECD guidelines or regional regulatory standards for toxicity study, and Good Laboratory Practice. RESULTS: When compared with the negative control, no genotoxic signs related to the AEPR treatment were observed in the AMES test up to 5000 µg/plate of AEPR and in the chromosomal aberration test up to 500 µg/ml of AEPR regardless of metabolic activation. Repeated oral administration of AEPR up to 5000 mg/kg/day for 2 days did not affect the body weight gains or mortalities of the experimental mice and did not induce any significant changes in the frequency of micronucleated polychromatic erythrocytes. CONCLUSIONS: The present study demonstrated that aqueous extract of Phragmitis rhizoma is safe regarding genotoxicity in an experimental model at least under the conditions tested. Further toxicity assessment in a human clinical study should be done to support the safe use of Phragmitis rhizoma by patients and healthcare providers.


Assuntos
Extratos Vegetais/toxicidade , Poaceae , Animais , Bioensaio , Linhagem Celular , Aberrações Cromossômicas , Cricetinae , Cricetulus , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Fibroblastos/efeitos dos fármacos , Pulmão/citologia , Masculino , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Rizoma , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética
6.
Biomed Pharmacother ; 116: 108987, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112870

RESUMO

BP10A is a novel two-herb medicine formula, consisting of Descurainiae sophia Semen and Peucedani praeruptorum Radix. This study was done to evaluate the antitumor efficacy of BP10A and its effect on the efficacy of the anticancer drugs oxaliplatin and irinotecan (CPT-11) in a colon tumor xenograft model. Chemical constituents from the ethanol extracts of BP10A were characterized with the ultra-performance liquid chromatography (UPLC) and each constituent was quantified with the UPLC-diode array detector method. Our study showed that BP10A exerted the cytotoxic effects in two colorectal cancer cell lines and its combination treatments with oxaliplatin or CPT-11 remarkably increased the in vitro cytotoxicity of each cancer drug assessed by the Ez-cytox assay. The in vivo antitumor activity of BP10A was evaluated in three colon cancer patient-derived tumor xenograft (PDTX) models with different genetic backgrounds. Oral administration with BP10A (250 and 500 mg/kg, daily) delayed tumor growth by 34-70% in the all PDTX models. Similarly, intraperitoneal injection of oxaliplatin (6 mg/kg) or CPT-11 (20 mg/kg) also suppressed tumor growth by 31.8-60.5% or by 24.3-50.4%, respectively. Furthermore, the combination treatment of BP10A with oxaliplatin or CPT-11 remarkably enhanced the antitumor activity of each anti-cancer drug and delayed tumor growth by 47.1-74.6% or by 74.4-82.9%, respectively. In accordance with the antitumor activity, the Ki-67 expression for tumor cell proliferation and the CD31 for angiogenesis were decreased, and TUNEL staining for tumor cell apoptosis was remarkably increased by the co-treatment of BP10A and the anticancer drugs as well as by each treatment of BP10A, oxaliplatin or CPT-11. Conclusively, BP10A has a strong tumor inhibitory effect against colon cancer and a synergistic effect with anticancer drugs, suggesting that BP10A could be considered as a good therapeutic candidate for the treatment of colon cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Irinotecano/química , Irinotecano/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxaliplatina/química , Oxaliplatina/farmacologia , Fitoterapia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Molecules ; 24(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934631

RESUMO

The dried fruits of Forsythia viridissima have been prescribed to relive fever, pain, vomiting, and nausea in traditional medicine. Oxaliplatin (LOHP) is used to treat advanced colorectal cancer; however, it frequently induces peripheral neuropathies. This study was done to evaluate the neuroprotective effects of an aqueous extract of Forsythia viridissima fruits (EFVF) and its major constituents. Chemical constituents from EFVF were characterized and quantified with the UHPLC-diode array detector method, and three major constituents were identified as arctiin, matairesinol, and arctigenin. The in vitro cytotoxicity was measured by the Ez-cytox viability assay, and the in vivo neuroprotection activity was evaluated by a von Frey test in two rodent animal models that were administered LOHP. EFVF significantly alleviated the LOHP-induced mechanical hypersensitivity in the induction model. EFVF also prevented the induction of mechanical hyperalgesia by LOHP in the pre- and co-treatment of LOHP and EFVF. Consistently, EFVF exerted protective effects against LOHP-induced neurotoxicity as well as inhibited neurite outgrowths in PC12 and dorsal root ganglion cells. Among the major components of EFVF, arctigenin and matairesinol exerted protective effects against LOHP-induced neurotoxicity. Therefore, EFVF may be useful for relieving or preventing LOHP-induced peripheral neuropathy in cancer patients undergoing chemotherapy with LOHP.


Assuntos
Forsythia/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/etiologia , Compostos Fitoquímicos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
8.
J Ethnopharmacol ; 235: 406-414, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30703490

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lithospermi radix has been prescribed in traditional folk medicine to treat diverse diseases like cancer. AIM OF THE STUDY: The present study assessed the sub-chronic oral toxicity of an aqueous extract of lithospermi radix (WLR) in Fischer 344 rats over a period of 13 weeks. MATERIALS AND METHODS: The chemical compositions of WLR were analyzed using ultra-high performance liquid chromatography (UHPLC). WLR was daily administered to Fischer 344 rats at 0, 500, 1000, and 2000 mg/kg body weights (bw) for 13 weeks via oral gavage. Changes in mortalities, body weights, and intakes of food and water were monitored during the WLR treatment period. Urine was collected and analyzed 12 h before necropsy. Organ weights, hematological parameters, and plasma biochemical parameters were determined along with histopathological examination. RESULTS: When compared with the normal control group, no remarkable toxic signs or parameter variations related with WLR treatment were observed in mortality, body weights, organ weights, food and water consumptions, urinalysis, hematological and plasma biochemical analyses, and histopathological examination. Mortalities observed in one male at 2000 mg/kg bw and three females at 1000 mg/kg bw were not related with WLR treatment because no gross findings of toxicity were observed in both morphological and histological examination. Some significant changes in clinical parameters or histological lesions observed in WLR-treated animals were not related with WLR treatment because the differences were marginal and did not show dose-dependent or directional changes. CONCLUSIONS: Based on these findings, the calculated no-observed-adverse-effect-level (NOAEL) in rats was higher than 2000 mg/kg bw.


Assuntos
Lithospermum/química , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/toxicidade , Testes de Toxicidade Subcrônica , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Masculino , Medicina Tradicional , Nível de Efeito Adverso não Observado , Extratos Vegetais/administração & dosagem , Raízes de Plantas , Ratos , Ratos Endogâmicos F344
9.
J Pediatr ; 204: 177-182.e1, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30297292

RESUMO

OBJECTIVE: To determine factors associated with adverse outcomes among febrile young infants with invasive bacterial infections (IBIs) (ie, bacteremia and/or bacterial meningitis). STUDY DESIGN: Multicenter, retrospective cohort study (July 2011-June 2016) of febrile infants ≤60 days of age with pathogenic bacterial growth in blood and/or cerebrospinal fluid. Subjects were identified by query of local microbiology laboratory and/or electronic medical record systems, and clinical data were extracted by medical record review. Mixed-effect logistic regression was employed to determine clinical factors associated with 30-day adverse outcomes, which were defined as death, neurologic sequelae, mechanical ventilation, or vasoactive medication receipt. RESULTS: Three hundred fifty infants met inclusion criteria; 279 (79.7%) with bacteremia without meningitis and 71 (20.3%) with bacterial meningitis. Forty-two (12.0%) infants had a 30-day adverse outcome: 29 of 71 (40.8%) with bacterial meningitis vs 13 of 279 (4.7%) with bacteremia without meningitis (36.2% difference, 95% CI 25.1%-48.0%; P < .001). On adjusted analysis, bacterial meningitis (aOR 16.3, 95% CI 6.5-41.0; P < .001), prematurity (aOR 7.1, 95% CI 2.6-19.7; P < .001), and ill appearance (aOR 3.8, 95% CI 1.6-9.1; P = .002) were associated with adverse outcomes. Among infants who were born at term, not ill appearing, and had bacteremia without meningitis, only 2 of 184 (1.1%) had adverse outcomes, and there were no deaths. CONCLUSIONS: Among febrile infants ≤60 days old with IBI, prematurity, ill appearance, and bacterial meningitis (vs bacteremia without meningitis) were associated with adverse outcomes. These factors can inform clinical decision-making for febrile young infants with IBI.


Assuntos
Bacteriemia/complicações , Febre/complicações , Meningites Bacterianas/complicações , Antibacterianos/administração & dosagem , Bacteriemia/mortalidade , Estudos de Coortes , Feminino , Febre/mortalidade , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Masculino , Meningites Bacterianas/mortalidade , Estudos Retrospectivos , Fatores de Risco
10.
Pain Manag Nurs ; 20(3): 185-191, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30527857

RESUMO

OBJECTIVE: The objective of this paper is to review the available literature regarding the use of cannabis and cannabinoids in adult oncologic pain management. DESIGN AND DATA SOURCES: A integrative review was conducted on March 1, 2018 using PubMed, MEDLINE, CINAHL, Embase, and Scopus. A snowball method was used to extract studies included in systematic reviews that were not included in the primary literature search. REVIEW METHOD: Articles reviewed address the use of cannabinoids or cannabis for pain management in oncology patients, either as stand- alone or adjuvant therapy. RESULTS: The final number of articles included is nine articles. Of the nine studies reviewed, eight reviewed the effect of the cannabinoid THC on cancer pain, and one study reviewed the use of medicinally available whole plant cannabis. The following study types were included: multiple multi-center, randomized, placebo- controlled trials and two prospective observational survey studies. RESULTS AND CONCLUSIONS: Of the eight studies that reviewed the effect of the cannabinoid THC, five found THC to be more effective than placebo, one found THC to be more effective than placebo in American patients but ineffective in patients from other countries, and two found THC to be no more effective than placebo. The study that reviewed the effect of the whole plant cannabis found that there was a significant decrease in pain among those patients smoking cannabis. NURSING PRACTICE IMPLICATIONS: The lack of evidence in this field of research suggests a need to change policy surrounding cannabis research.


Assuntos
Dor do Câncer/tratamento farmacológico , Canabinoides/uso terapêutico , Cannabis/efeitos adversos , Adulto , Analgésicos/uso terapêutico , Dor do Câncer/fisiopatologia , Canabinoides/normas , Humanos , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Manejo da Dor/normas
11.
Leuk Res Rep ; 7: 36-39, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28462084

RESUMO

Anthracyclines constitute the backbone of intensive adult acute myeloid leukemia (AML) therapy. Cardiotoxicity is one of its most serious adverse effects, and its incidence increases with cumulative dose. Dexrazoxane is a cardioprotective agent used in conjunction with anthracycline therapy. There is limited data of its usage in adult AML patients. We report the outcomes of six older adults at high risk of anthracycline-induced cardiotoxicity who received dexrazoxane during induction/re-induction therapy. Five had preserved left-ventricular function while two proceeded onto stem-cell transplantation. Additional investigation of dexrazoxane in adult leukemia therapy is warranted, particularly in older patients at highest risk for cardiovascular mortality.

12.
Genetics ; 206(3): 1479-1493, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28495961

RESUMO

Mutations in the Presenilin genes are the major genetic cause of Alzheimer's disease. Presenilin and Nicastrin are essential components of γ-secretase, a multi-subunit protease that cleaves Type I transmembrane proteins. Genetic studies in mice previously demonstrated that conditional inactivation of Presenilin or Nicastrin in excitatory neurons of the postnatal forebrain results in memory deficits, synaptic impairment, and age-dependent neurodegeneration. The roles of Drosophila Presenilin (Psn) and Nicastrin (Nct) in the adult fly brain, however, are unknown. To knockdown (KD) Psn or Nct selectively in neurons of the adult brain, we generated multiple shRNA lines. Using a ubiquitous driver, these shRNA lines resulted in 80-90% reduction of mRNA and pupal lethality-a phenotype that is shared with Psn and Nct mutants carrying nonsense mutations. Furthermore, expression of these shRNAs in the wing disc caused notching wing phenotypes, which are also shared with Psn and Nct mutants. Similar to Nct, neuron-specific Psn KD using two independent shRNA lines led to early mortality and rough eye phenotypes, which were rescued by a fly Psn transgene. Interestingly, conditional KD (cKD) of Psn or Nct in adult neurons using the elav-Gal4 and tubulin-Gal80ts system caused shortened lifespan, climbing defects, increases in apoptosis, and age-dependent neurodegeneration. Together, these findings demonstrate that, similar to their mammalian counterparts, Drosophila Psn and Nct are required for neuronal survival during aging and normal lifespan, highlighting an evolutionarily conserved role of Presenilin in neuronal protection in the aging brain.


Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , Proteínas de Drosophila/genética , Neurônios/metabolismo , Presenilinas/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Códon sem Sentido , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Evolução Molecular , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Neurônios/citologia , Presenilinas/metabolismo
13.
Cancers (Basel) ; 8(12)2016 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-27886124

RESUMO

Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field.

14.
Sci Rep ; 5: 14205, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26391485

RESUMO

Curcumin has diverse biological activities, but is known to undergo rapid metabolism via reduction of vinylic double bonds and phase II conjugation. To prevent reductive metabolism of curcumin, we introduced a methyl group at both C2 and C6 positions (compound 1) or at the C2 position (compound 2) of curcumin, creating steric hindrance on double bonds against metabolizing enzymes. As predicted, these compounds were resistant to reduction by alcohol dehydrogenase. Compound 1 was further evaluated for its antiangiogenesis activity in vitro and in vivo. It exhibited significantly greater inhibitory activity than curcumin against endothelial cell migration, invasion, and tube formation. Similarly, the in vivo Matrigel plug assay in C57BL/6 mice showed more pronounced reduction of blood vessels in the plugs containing 1 than those containing curcumin. Moreover, 1 suppressed tumor growth more effectively than curcumin in a U87MG mouse xenograft model by inhibiting angiogenesis. In vivo metabolite analysis by liquid chromatography/mass spectrometry demonstrated that 1 underwent markedly slower reductive metabolism than curcumin. Taken together, our results indicate that 1 has enhanced antiangiogenesis activity and suppression of tumor growth compared with curcumin, reflecting diminished reductive metabolism owing to the introduction of methyl groups at the C2 and C6 positions of curcumin.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Carbono/química , Curcumina/química , Curcumina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Álcool Desidrogenase/química , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/síntese química , Células Endoteliais/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metilação , Camundongos , Neovascularização Patológica/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Prim Prev ; 34(1-2): 59-69, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23377881

RESUMO

The purpose of this study was to examine human papillomavirus (HPV) knowledge and vaccine acceptability in a convenience sample of immigrant Hispanic men, many of whom are parents of adolescents. Data on 189 male callers were collected from the National Cancer Institute's Cancer Information Service Spanish-language call center. Most participants were willing to vaccinate their adolescent son (87.5%) or daughter (78.8%) against HPV. However, among this sample, awareness of HPV was low and knowledge of key risk factors varied. These findings can help guide the development of culturally informed educational efforts aimed at increasing informed decision-making about HPV vaccination among Hispanic fathers.


Assuntos
Pai/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Hispano-Americanos/psicologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Adulto , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade
16.
Cancer Res ; 70(24): 10121-30, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159634

RESUMO

NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8(+) T cells). In this study, we explored the potential therapeutic utility of this intersection by fusing the murine NKG2D ligand Rae-1ß to the 3' end of an anti-HER2 IgG3 antibody containing an intact Fc domain (anti-HER2 IgG3-Rae-1ß), thereby targeting an NK cell activation signal to HER2+ breast tumor cells. The antitumor efficacy of this anti-HER2-Rae-1ß fusion protein was examined in a mouse mammary tumor model engineered to express HER2 (EMT6-HER2 cells). We observed an enhanced cytotoxic response of NK effectors against EMT-HER2 cells in vitro. Mice implanted on one flank with EMT6-HER2 cells and contralaterally with control EMT6 cells exhibited rapid regression of EMT6-HER2 tumors but delayed regression of contralateral EMT6 tumors. IFNγ was implicated, given a lack of antitumor efficacy in IFNγ(-/-) mice. Depletion of either NK cells or CD8(+) T cells abrogated tumor growth inhibition, suggesting essential roles for each in the observed antitumor activity. Mice rejecting EMT6-HER2 tumors after anti-HER2-Rae-1ß treatment showed markedly decreased tumor growth when rechallenged with EMT6-HER2 or EMT6 cells, whereas both EMT6 and EMT6-HER2 cells grew in control mice, indicating the development of an adaptive memory response. Our findings demonstrate that administration of an antibody-NKG2D ligand fusion protein can enhance innate and adaptive immune antitumor responses, also evoking additional nontargeted antigens to enhance the potential clinical utility of this approach.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor ErbB-2/imunologia , Proteínas Recombinantes de Fusão/imunologia , Imunidade Adaptativa , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade Inata , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Receptor ErbB-2/antagonistas & inibidores , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia
17.
Pain ; 148(2): 237-46, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20005044

RESUMO

Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund's adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCgamma and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal-glial-cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCgamma and pERK2 are increased. At 96h the expression of the proinflammatory cytokine, IL-1beta, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCgamma and the induction of pERK2 and IL-1beta in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies.


Assuntos
Inflamação/complicações , Neurônios/metabolismo , Limiar da Dor/fisiologia , Dor/etiologia , Dor/patologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Antirreumáticos/farmacologia , Astrócitos/metabolismo , Modelos Animais de Doenças , Feminino , Adjuvante de Freund , Lateralidade Funcional , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dor/tratamento farmacológico , Dor/genética , Fosfopiruvato Hidratase/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Receptores de N-Metil-D-Aspartato/deficiência , Medula Espinal/patologia , Fatores de Tempo
18.
J Neurosci ; 28(52): 14087-96, 2008 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-19109491

RESUMO

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling in the spinal cord dorsal horn (SCDH) has been implicated in injury-induced pain hypersensitivity. Available ERK pathway inhibitors cannot distinguish between ERK1 and ERK2, nor can they differentially target the expression of neuronal or glial ERK1/2. We selectively inhibited the expression of ERK2 in neurons of the adult mouse SCDH by use of an ERK2 small interfering RNA (siRNA) delivered by a neurotropic adenoassociated viral vector. In situ hybridization revealed a siRNA vector-induced decrease in ERK2 mRNA in the ipsilateral SCDH. Immunohistochemistry showed a decreased neuronal phospho-ERK1/2 (pERK1/2), and Western blot analysis revealed that both ERK2 expression and phosphorylation were reduced by the siRNA vector. In contrast, basal ERK1 expression was not affected, although pERK1 was slightly increased. The siRNA vector-induced knockdown of ERK2 expression in the SCDH did not alter the baseline mechanical or thermal paw withdrawal thresholds. Hindpaw intraplantar injection of complete Freund's adjuvant (CFA) produced peripheral inflammation, mechanical allodynia, and thermal hyperalgesia in vector control animals that persisted for at least 96 h. It also caused an increase in SCDH ERK1 and ERK2 levels at 96 h and pERK1 and pERK2 levels at 1 and 96 h. The ERK2 siRNA vector prevented changes in ERK1, ERK2, and pERK2. In addition, the siRNA vector protected the animals from developing mechanical allodynia and thermal hyperalgesia throughout the 96 h after CFA. These findings indicate that ERK2 in the SCDH neurons is critical for the development of inflammatory pain hypersensitivity.


Assuntos
Hiperalgesia/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Limiar da Dor/fisiologia , Células do Corno Posterior/enzimologia , Animais , Dinorfinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Adjuvante de Freund/efeitos adversos , Lateralidade Funcional , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Fosfopiruvato Hidratase/metabolismo , Fosforilação , Células do Corno Posterior/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Medula Espinal/citologia
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