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1.
Int Heart J ; 60(5): 1176-1183, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564708

RESUMO

Recently, the potential role of gut microbiome (GM) in cardiovascular diseases has been revealed. Heart failure (HF) is one of the most prevalent cardiovascular diseases worldwide; however, whether GM dysbiosis participates in the development of HF remains largely unknown. This study aimed to investigate the specific changes in GM composition and function in isoproterenol (ISO)-induced HF in rats.The rats were divided into C (control), 4w-HF (ISO, 2.5 mg/kg/day for 4 weeks, intraperitoneally), and 2w-HF (ISO, 2.5 mg/kg/day for 2 weeks, intraperitoneally) groups. The cardiac structure and function in rats were assessed, and metagenomic analyses were then performed. Compared with the healthy control group, we found that the Shannon diversity index and microbial gene count in the 4w-HF and 2w-HF groups was drastically decreased. High-throughput sequencing showed that the three groups differed in intestinal bacterial community composition. Overgrowth of bacteria, such as Prevotella, was observed in the 4w-HF group, with reduced growth of bacteria, such as Roseburia, Lactobacillus, and Butyrivibrio, associated with healthy status compared with the C group on the genus level. Concomitant with the alteration of GM composition, underrepresentation of health-linked microbial function was observed in both the 4w-HF and 2w-HF groups compared with the C group.Iso-induced HF rats showed a significant decrease in the diversity and richness of the intestinal microbiome, with a downregulation of the key intestinal bacterial groups and overgrowth of bacteria considered to be involved in inflammatory responses as well as a decrease in health-linked microbial function. Our data indicated that altered GM may be a potential player in the pathogenesis and progression of HF.


Assuntos
Bactérias/classificação , Microbioma Gastrointestinal/efeitos dos fármacos , Insuficiência Cardíaca/microbiologia , Isoproterenol/efeitos adversos , Metagenômica/métodos , Animais , Bactérias/genética , Modelos Animais de Doenças , Ecocardiografia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico por imagem , Sequenciamento de Nucleotídeos em Larga Escala , Injeções Intraperitoneais , Isoproterenol/farmacologia , Masculino , Filogenia , Ratos , Análise de Sequência de DNA
2.
Chem Commun (Camb) ; 55(75): 11263-11266, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31475257

RESUMO

A reversible fluorescent probe (NP) for sensing SO2 and FA was rationally constructed. With the outstanding attributes of NP, the fluctuation of endogenous SO2 and FA was successfully traced, not only at the cellular level, but also in living mice for the first time. Significantly, it was first found that the interaction of SO2 and FA can attenuate the cytotoxicity.


Assuntos
Corantes Fluorescentes/química , Formaldeído/análise , Dióxido de Enxofre/análise , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/síntese química , Formaldeído/farmacologia , Células HeLa , Humanos , Injeções Intraperitoneais , Camundongos , Estrutura Molecular , Imagem Óptica , Espectrometria de Fluorescência , Dióxido de Enxofre/farmacologia
3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(8): 994-997, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31537226

RESUMO

OBJECTIVE: To establish septic myocardial inhibition rat model by echocardiography. METHODS: Twenty adult male Sprague-Dawley (SD) rats were divided into control group and model group according to the random number table method, with 10 rats in each group. The rat model of septic myocardial inhibition was reproduced by intraperitoneal injection of 10 mg/kg lipopolysaccharide, while the control group was given the same volume of saline. The left ventricular end-diastolic diameter (LVDd), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic diameter (LVDs), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), right ventricular end-diastolic diameter (RVDd), right ventricular end-systolic diameter (RVDs), heart rate (HR), positive pulmonary artery flow rate and aortic flow rate were measured at 8 hours after model establishment by echocardiography. Then the rats were sacrificed to harvest serum and myocardial tissue. The levels of serum tumor necrosis factor-α (TNF-α), nuclear factor-ΚB (NF-ΚB), interleukin-1 (IL-1), cardiac troponin I (cTnI) and B-type brain natriuretic peptide (BNP) were measured by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of TNF-α, IL-1 and NF-ΚB in myocardium were detected by real-time polymerase chain reaction (real-time PCR). The pathological changes of myocardium were observed by hematoxylin-eosin (HE) staining under light microscope. RESULTS: Compared with control group, myocardial inhibition was obviously observed in model group, manifesting as enlargement of overall shape of heart, and prominent increase of HR (bpm: 449.0±21.1 vs. 356.7±23.3, P < 0.01); left ventricular and right ventricular functions were affected, LVDd, LVDs, LVEDV, LVESV were enlarged [LVDd (mm): 10.03±0.95 vs. 7.04±0.71, LVDs (mm): 5.95±0.71 vs. 3.07±0.05, LVEDV (mL): 2.11±0.53 vs. 0.81±0.21, LVESV (mL): 0.51±0.16 vs. 0.07±0.01, all P < 0.05], LVEF was significantly decreased (0.760±0.046 vs. 0.901±0.025, P < 0.01), RVDd was significantly increased (mm: 4.48±0.58 vs. 3.22±0.20, P < 0.05), and positive pulmonary artery velocity was significantly decreased (cm/s: 64.2±9.3 vs. 89.0±0.8, P < 0.05). Compared with control group, the levels of serum NF-ΚB, TNF-α, IL-1, BNP and cTnI in model group were significantly increased [NF-ΚB (ng/L): 103.84±6.55 vs. 57.29±41.34, TNF-α (ng/L): 1 198.32±164.07 vs. 835.45±24.01, IL-1 (ng/L): 1 089.90±221.96 vs. 746.19±165.83, BNP (ng/L): 1 097.36±293.84 vs. 454.71±197.79, cTnI (ng/L): 6 938.59±1 400.21 vs. 3 731.90±1 349.31, all P < 0.01], the mRNA expressions of TNF-α, NF-ΚB and IL-1 in myocardial tissue were significantly increased (2-ΔΔCT: 1.50±0.42 vs. 0.71±0.40, 1.10±0.17 vs. 0.63±0.06, 1.77±0.67 vs. 0.10±0.03, all P < 0.05). It was shown by HE staining that the structure of myocardial tissue in control group was distinct, the arrangement of myocardial fibers was neat, and transverse was clear; the structure of myocardial tissue in model group was loose, blurred, and the cells were swollen, with obvious pathological changes. CONCLUSIONS: Cardiac function was assessed by echocardiography, expression of inflammatory factors, myocardial markers and pathological changes. It was verified that intraperitoneal injection of 10 mg/kg endotoxin could successfully prepare a rat model of septic myocardial inhibition.


Assuntos
Endotoxinas/toxicidade , Injeções Intraperitoneais , Modelos Animais , Miocárdio , Animais , Masculino , NF-kappa B , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue
4.
J Surg Oncol ; 120(4): 794-802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31309588

RESUMO

BACKGROUND AND OBJECTIVES: To review long-term survival outcomes of patients with Peritoneal metastasis (PM) who underwent colorectal cancer (CRS) and intraperitoneal chemotherapy (PIC). METHODS: Patients that underwent CRS, with or without PIC, from January 1996 to March 2018 at the Peritonectomy Unit of St. George Hospital, Sydney were retrospectively analyzed from a prospectively maintained database. RESULTS: The study comprised of 1225 cases, including 687 females (56.1%) and 538 males (43.9%). Diagnoses included CRC (n = 363), followed by HAMN (n = 317), LAMN (n = 297), mesothelioma (n = 101), ovarian cancer (n = 55), and others including gastric, sarcoma, and neuroendocrine tumor (n = 92). The median OS, 5- and 10-year survivals for CRC were 35 months, 33% and 8%, respectively. Patients with LAMN, in relative to HAMN, experienced a higher median OS, 5- and 10-year survivals (248 months vs 63 months; 82% vs 52% and 59% vs 28%). The median OS for mesothelioma was 60 months with 5- and 10-year survivals of 48% and 19%, respectively. In ovarian cancer, the median OS was 30 months with 5- and 10-year survivals of 26% and 10%, respectively. For the remaining histological diagnoses, median OS and 5-year survival were 28 months and 27%, respectively. CONCLUSION: Our large-cohort data showed that CRS/PIC can provide long-term survival benefit to patients with PM of gastrointestinal and ovarian origin.


Assuntos
Neoplasias do Apêndice/mortalidade , Quimioterapia do Câncer por Perfusão Regional/mortalidade , Neoplasias Colorretais/mortalidade , Procedimentos Cirúrgicos de Citorredução/mortalidade , Neoplasias Pulmonares/mortalidade , Mesotelioma/mortalidade , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intraperitoneais , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/patologia , Mesotelioma/terapia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Assistência Perioperatória , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
5.
APMIS ; 127(10): 688-695, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344274

RESUMO

Acetylshikonin has long been known as an anti-inflammatory and antioxidative reagent. However, the anti-allergic effect has not been studied. The aim of this study was to evaluate the effect of acetylshikonin on allergic rhinitis (AR) in mice. Mice were sensitized by intraperitoneal injection of OVA and aluminum hydroxide and challenged with intranasal instillation of OVA. Acetylshikonin was administered orally after nasal cavities challenge. Severity of allergic rhinitis was assessed according to nasal symptoms; serum OVA-specific immunoglobulin E (IgE), IgG1, and IgG2a level; and interleukin (IL)-4, IL-10, IL-5, IL-13, TNF-α, IL-12, and interferon (INF)-γ levels in nasal lavage fluid (NALF). Additionally, the histological change and the release of histamine in serum and nasal lavage fluid were evaluated by acid-Schiff stain and ELISA. Acetylshikonin attenuated manifestation of nasal symptoms in sensitized mice and inhibited production of Th2-related OVA-specific IgE, IgG1, and Th2 cell-produced IL-4, IL-5, IL-13, and mast cell produced histamine; however, it had no effect on Th1 cell-produced cytokines, like INF-γ. In addition, the degree of inflammatory cell infiltration and goblet cell hyperplasia was attenuated by acetylshikonin treatment. Our results suggest that acetylshikonin effectively reduces allergic inflammation in a mouse model of allergic rhinitis by its anti-allergic and anti-inflammatory properties.


Assuntos
Antraquinonas/administração & dosagem , Citocinas/antagonistas & inibidores , Liberação de Histamina/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Mastócitos/efeitos dos fármacos , Rinite Alérgica/tratamento farmacológico , Células Th2/efeitos dos fármacos , Administração Oral , Alérgenos/administração & dosagem , Animais , Modelos Animais de Doenças , Injeções Intraperitoneais , Camundongos , Ovalbumina/administração & dosagem , Rinite Alérgica/induzido quimicamente , Rinite Alérgica/patologia , Resultado do Tratamento
6.
Cancer Sci ; 110(8): 2485-2492, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31265162

RESUMO

Multi-walled carbon nanotube-7 (MWCNT-7) fibers are biopersistent and have a structure similar to asbestos. MWCNT-7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT-7 developed lung tumors. MWCNT-N, which is similar to MWCNT-7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans-tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT-7 when administered by the TIPS method. Ten-week-old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 µg/mL MWCNT-7 or 0.250 µg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT-7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT-7 group was significantly higher than in the vehicle or crocidolite groups.


Assuntos
Neoplasias Pulmonares/induzido quimicamente , Pulmão/efeitos dos fármacos , Mesotelioma/induzido quimicamente , Nanotubos de Carbono/efeitos adversos , Neoplasias Pleurais/induzido quimicamente , Animais , Asbesto Crocidolita/efeitos adversos , Injeções Intraperitoneais/métodos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Ratos , Ratos Endogâmicos F344 , Traqueia/efeitos dos fármacos , Traqueia/patologia
7.
Pharm Res ; 36(9): 126, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236829

RESUMO

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is hypothesized to have advantages such as enhancing tissue uptake, distributing drugs homogeneously within the closed and expanded abdominal cavity and higher local concentration of drugs in the peritoneal cavity. However, the clinical trials of PIPAC so far are limited to liquid chemotherapeutic solution, and the applicability of biomolecules (such as mRNA, siRNA and oligonucleotide) is not known. We aimed to investigate the feasibility of administrating mRNA lipoplexes to the peritoneal cavity via high pressure nebulization. METHODS: We firstly investigated the influences of nebulization on physicochemical properties and in vitro transfection efficiency of mRNA lipoplexes. Then, mRNA lipoplexes were delivered to healthy rats through intravenous injection, intraperitoneal injection and PIPAC, respectively. RESULTS: mRNA lipoplexes can withstand the high pressure applied during the PIPAC procedure in vitro. Bioluminescence localized to the peritoneal cavity of rats after administration by IP injection and nebulization, while intravenous injection mainly induced protein expression in the spleen. CONCLUSION: This study demonstrated that local nebulization is feasible to apply mRNA complexes in the peritoneal cavity during a PIPAC procedure.


Assuntos
Lipídeos/química , Lipossomos/química , Nanopartículas/química , RNA Mensageiro/administração & dosagem , Aerossóis , Animais , Linhagem Celular Tumoral , Composição de Medicamentos , Estudos de Viabilidade , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Nebulizadores e Vaporizadores , Cavidade Peritoneal , Pressão , Ratos Nus
8.
Chin J Traumatol ; 22(3): 161-165, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31056470

RESUMO

PURPOSE: To investigate whether dexmedetomidine (Dex) can reduce the production of inflammatory factor IL-1ß by inhibiting the activation of NLRP3 inflammasome in hippocampal microglia, thereby alleviating the inflammatory response of the central nervous system induced by surgical injury. METHODS: Exploratory laparotomy was used in experimental models in this study. Totally 48 Sprague Dawley male rats were randomly divided into 4 groups (n = 12 for each), respectively sham control (group A), laparotomy only (group B); and Dex treatment with different doses of 5 µg/kg (group D1) or 10 µg/kg (group D2). Rats in groups D1 and D2 were intraperitoneally injected with corresponding doses of Dex every 6 h. The rats were sacrificed 12 h after operation; the hippocampus tissues were isolated, and frozen sections were made. The microglia activation was estimated by immunohistochemistry. The protein expression of NLRP3, caspase-1, ASC and IL-1ß were detected by immunoblotting. All data were presented as mean ± standard deviation, and independent sample t test was used to analyze the statistical difference between groups. RESULTS: The activated microglia in the hippocampus of the rats significantly increased after laparotomy (group B vs. sham control, p < 0.01). After Dex treatment, the number was decreased in a dose-dependent way (group D1 vs. D2, p < 0.05), however the activated microglia in both groups were still higher than that of sham controls (both p < 0.05). Further Western blot analysis showed that the protein expression levels of NLRP3, caspase-1, ASC and downstream cytokine IL-1ß in the hippocampus from the laparotomy group were significantly higher than those of the sham control group (all p < 0.01). The elevated expression of these proteins was relieved after Dex treatment, also in a dose-dependent way (D2 vs. D1 group, p < 0.05). CONCLUSION: Dex can inhibit the activation of microglia and NLRP3 inflammasome in the hippocampus of rats after operation, and the synthesis and secretion of IL-1ß are also reduced in a dose-dependent manner by using Dex. Hence, Dex can alleviate inflammation activation on the central nervous system induced by surgical injury.


Assuntos
Dexmedetomidina/farmacologia , Hipocampo/metabolismo , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Laparotomia/efeitos adversos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Injeções Intraperitoneais , Masculino , Ratos Sprague-Dawley , Fatores de Tempo
9.
Invest Ophthalmol Vis Sci ; 60(6): 2072-2082, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091314

RESUMO

Purpose: Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) reduces aqueous humor outflow, which likely contributes to elevation of IOP in primary open-angle glaucoma (POAG). Salidroside, a phenolic glycoside isolated from Rhodiola rosea is reported to prevent profibrotic responses by inhibiting Smad signaling pathway activated by TGF-ß in liver, lung, and kidney tissues. We tested if salidroside can (1) inhibit TGF-ß2-induced ECM expression in cultured human TM cells, and (2) lower TGF-ß2-induced ocular hypertension in the mouse. Methods: Cultured human TM cells stimulated with 5 ng/mL TGF-ß2 for 48 hours were treated with salidroside for 24 hours. The expressions of fibronectin (FN), collagen type IV (COL-IV), and laminin (LN) were evaluated by quantitative PCR, Western blot, and immunocytochemistry. BALB/cJ mice were injected intravitreally with an adenoviral vector encoding a bioactive mutant of TGF-ß2 (Ad.hTGF-ß2226/228) in one eye to induce ocular hypertension, with the uninjected contralateral or Ad.Empty-injected eyes serving as controls. Mice were treated with a daily intraperitoneal injection of 40 mg/kg salidroside. Conscious mouse IOP values were measured using a TonoLab rebound tonometer. Results: In cultured human TM cells, treatment with TGF-ß2 increased expressions of FN, COL-IV, and LN, as assessed by quantitative PCR, Western blotting, and immunocytochemistry, all of which were significantly and completely ameliorated by 30 µM salidroside. Daily intraperitoneal injections of salidroside (40 mg/kg), starting either at day 0 (same day as Ad.hTGF-ß2226/228 injection) or at day 14, significantly lowered TGF-ß2-induced ocular hypertension in the mouse. In contrast, salidroside did not affect IOP of control eyes. Conclusions: These results demonstrated that salidroside is capable of minimizing TGF-ß2-induced ECM expression in cultured human TM cells. It also reduced TGF-ß2-induced ocular hypertension in the mouse. These findings indicate that this phenolic glycoside may be useful as a novel treatment for POAG.


Assuntos
Matriz Extracelular/metabolismo , Glucosídeos/farmacologia , Pressão Intraocular/efeitos dos fármacos , Hipertensão Ocular/tratamento farmacológico , Fenóis/farmacologia , Malha Trabecular/efeitos dos fármacos , Animais , Células Cultivadas , Colágeno Tipo IV/metabolismo , Fibronectinas/metabolismo , Humanos , Injeções Intraperitoneais , Laminina/metabolismo , Camundongos , Hipertensão Ocular/metabolismo , Malha Trabecular/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/farmacologia
10.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096551

RESUMO

We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A2 activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present study evaluated the effect of these Prdx6-inhibitory peptides (PIP) in a mouse (C57Bl/6) model of acute lung injury following lipopolysaccharide (LPS) administration. All three peptides (PIP-1, 2 and 3) similarly inhibited the production of reactive O2 species (ROS) in isolated mouse lungs as detected by the oxidation of Amplex red. PIP-2 inhibited both the increased phospholipase A2 activity of Prdx6 and lung reactive oxygen species (ROS) production following treatment of mice with intratracheal LPS (5 µg/g body wt.). Pre-treatment of mice with PIP-2 prevented LPS-mediated lung injury while treatment with PIP-2 at 12 or 16 h after LPS administration led to reversal of lung injury when evaluated 12 or 8 h later, respectively. With a higher dose of LPS (15 µg/g body wt.), mortality was 100% at 48 h in untreated mice but only 28% in mice that were treated at 12-24 h intervals, with PIP-2 beginning at 12 h after LPS administration. Treatment with PIP-2 also markedly decreased mortality after intraperitoneal LPS (15 µg/g body wt.), used as a model of sepsis. This study shows the dramatic effectiveness of a peptide inhibitor of Prdx6 against lung injury and mouse mortality in LPS models. We propose that the PIP nonapeptides may be a useful modality to prevent or to treat human ALI.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/prevenção & controle , Lipopolissacarídeos/efeitos adversos , NADPH Oxidase 2/metabolismo , Peptídeos/metabolismo , Peroxirredoxina VI/farmacologia , Inibidores de Fosfolipase A2/farmacologia , Fosfolipases A2/metabolismo , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/mortalidade , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Injeções Intraperitoneais , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Peroxirredoxina VI/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Cancer Sci ; 110(7): 2247-2257, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31099446

RESUMO

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Furanos/administração & dosagem , Glioblastoma/tratamento farmacológico , Cetonas/administração & dosagem , Regiões Promotoras Genéticas/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Feminino , Furanos/farmacologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Humanos , Injeções Intraperitoneais , Cetonas/farmacologia , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Telomerase/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
BMC Cancer ; 19(1): 424, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064330

RESUMO

BACKGROUND: pressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model. METHODS: laparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging. RESULTS: PIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 µm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 µm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 106 cells, miliary PM was observed in all animals. PIPAC was feasible and well supported in these tumor bearing animals. CONCLUSIONS: we propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.


Assuntos
Antineoplásicos/administração & dosagem , Laparoscopia/métodos , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Aerossóis/administração & dosagem , Animais , Linhagem Celular Tumoral , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Feminino , Humanos , Injeções Intraperitoneais/efeitos adversos , Injeções Intraperitoneais/métodos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Peritônio/efeitos dos fármacos , Peritônio/patologia , Pressão , Ratos , Ratos Nus , Ratos Wistar , Eletricidade Estática
13.
Indian J Ophthalmol ; 67(6): 801-805, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31124490

RESUMO

Purpose: To evaluate the effect of cyanidin-3-glucoside (C3G) in oxygen-induced retinopathy (OIR) mouse model. Methods: In this experimental study, 10 C57BL / 6J type mice exposed to room air comprised two control groups (n = 5 each; a negative control and a group receiving intravitreal sterile dimethyl sulfoxide [IVS DMSO]). Thirty C57BL / 6J type mice exposed to 75% ± 2% oxygen from postnatal day 7 to postnatal day 12 comprised the OIR groups. On postnatal day 12, these mice were randomized into six groups (n = 5 each): two OIR control groups (negative control and IVS DMSO), two intravitreal C3G groups (300 and 600 ng/µL), and two intraperitoneal C3G groups (0.05 and 0.1 mg/kg). We quantified neovascularization by counting endothelial cell proliferation on the vitreal side of the inner limiting membrane of the retina and examined histological and ultrastructural changes via light and electron microscopy and apoptosis by terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling. Results: The intravitreal C3G groups yielded lower endothelial cell counts compared with the intravitreal DMSO group. The intraperitoneal high-dose group had lower cell counts compared with the OIR control groups. Electron microscopy revealed significantly less mitochondrial dysmorphology in intravitreal groups and the high-dose intraperitoneal mice. We noted no difference in apoptotic cell count between the controls, low-dose intravitreal, and both intraperitoneal groups. However, apoptotic cell count was significantly higher in the high-dose intravitreal group. Conclusion: C3G suppresses endothelial cell proliferation in an OIR mouse model, leads to a reduced hyperoxia-induced mitochondrial dysmorphology, but increases apoptotic cell death in high concentrations.


Assuntos
Antocianinas/administração & dosagem , Glicosídeos/administração & dosagem , Retina/patologia , Doenças Retinianas/tratamento farmacológico , Animais , Animais Recém-Nascidos , Apoptose , Proliferação de Células , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Injeções Intravítreas , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Oxigênio/toxicidade , Retina/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/patologia
14.
Invest Ophthalmol Vis Sci ; 60(5): 1604-1613, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995317

RESUMO

Purpose: We address the hypothesis that uncoupling protein 2 (UCP2), a cellular glucose regulator, delays physiologic retinal vascular development (PRVD) by interfering with glucose uptake through glucose transporter 1 (Glut1). Methods: In the rat 50/10 oxygen-induced retinopathy (OIR) model, retinal Glut1 and UCP2 were measured and compared to room air (RA)-raised pups at postnatal day 14 (p14). Pups in OIR and RA received intraperitoneal genipin, an UCP2 inhibitor, or control every other day from p3 until p13. Analyses at p14 included avascular/total retinal area (AVA), Western blots of retinal UCP2 and Glut1, and immunostaining of Glut1 in retinal cryosections. Intravitreal neovascular/total retinal area (IVNV) was analyzed at p18, and electroretinograms were performed at p26. Glut1 and phosphorylated VEGFR2 (p-VEGFR2), glucose uptake, adenosine triphosphate (ATP) production, and cell proliferation were measured in human retinal microvascular endothelial cells (hRMVECs) pretreated with genipin or transfected with UCP2siRNA, Glut1siRNA, or control siRNA when incubated with VEGF or PBS. Results: At p14, OIR pups had increased AVA with decreased Glut1 and increased UCP2 in the retina compared to RA retinas. Intraperitoneal genipin increased retinal Glut1 and reduced AVA. Compared to control, treatment with genipin or knockdown of UCP2 significantly increased Glut1, glucose uptake, ATP production, VEGF-induced p-VEGFR2 and cell proliferation in hRMVECs. Knockdown of Glut1 inhibited VEGF-induced p-VEGFR2. Genipin-treated OIR pups with decreased AVA at p14 had reduced IVNV at p18 and increased amplitudes in a- and b-waves at p26. Conclusions: Extending PRVD by increasing retinal endothelial glucose uptake may represent a strategy to prevent severe retinopathy of prematurity and vision loss.


Assuntos
Retinopatia Diabética/metabolismo , Endotélio Vascular/metabolismo , Glicólise/fisiologia , Vasos Retinianos/fisiologia , Proteína Desacopladora 2/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Inativação Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Injeções Intraperitoneais , Iridoides/farmacologia , Masculino , Oxigênio/toxicidade , Gravidez , Ratos , Ratos Sprague-Dawley , Transfecção , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Toxicol Lett ; 308: 50-55, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940550

RESUMO

Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide and potential chemical threat agent. Signs of TMDT poisoning include convulsions which can progress into status epilepticus and death. Although clinical reports clearly show that poisoning via food and drink is the main route of exposure, experimental studies have primarily utilized parenteral routes. Here we used two different modes of oral administration of TMDT and compared the toxic outcomes with two different parenteral routes. Adult male mice were given various doses of TMDT either perorally in peanut butter or cereal pellets, or injected intraperitoneally (i.p.) or subcutaneously (s.c.). All routes produced the complete TMDT syndrome including twitches, clonic and tonic-clonic seizures and death. However potencies varied with the following rank order: i.p. > s.c. > oral (cereal)>>oral (peanut butter). Our data clearly show that ingestion of TMDT with peanut butter markedly reduces the overall syndrome severity relative to oral exposure via cereals. No significant differences were observed by substituting peanut oil for water as a vehicle for i.p. administered TMDT. In conclusion, high vs low fat food can differentially affect TMDT onset of action, probably due to differences in availability from the gastrointestinal tract. These results should be considered when searching for effective treatments for TMDT poisoning.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/envenenamento , Modelos Animais de Doenças , Síndromes Neurotóxicas/etiologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Humanos , Injeções Intralinfáticas , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Envenenamento/etiologia
16.
Chem Biol Interact ; 306: 70-77, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980806

RESUMO

PURPOSE: Skeletal muscle is severely affected in diabetes leading to muscle atrophy. Previously we reported the role of ER stress in muscle atrophy due to hyperglycemia. Hence, in the present study, we investigated the effect of a classical ER stress inhibitor, 4-phenylbutyric acid (PBA), on muscle atrophy in diabetic rats. METHODS: Diabetes was induced in male rats by streptozotocin, and PBA was administered (40 mg/kg/day; intraperitoneal) after two months of diabetes for two more months. Gastrocnemius muscle is collected after four months of experimental period. The cross-sectional area of myocytes was measured on Hematoxylin and Eosin stained muscle sections. Protein levels of ER stress markers, ubiquitin-proteasome system (UPS) components, and apoptosis were analysed by immunoblot. Proteasomal activity and apoptotic cells were measured. RESULTS: ER stress markers (GRP78, ATF6, ATF4 and CHOP) that are elevated in diabetes are decreased with PBA treatment. PBA also averted diabetes-induced alterations in UPS (higher levels of E1, atrogin-1, UCHL1 and UCHL5, accumulation of ubiquitinated proteins and increased proteasomal activity). Apoptosis mediators-p53, BAX, and cleaved caspase-3 protein levels, and TUNEL positive cells were decreased in PBA treated diabetic rats. PBA notably improved the muscle-cross sectional area. CONCLUSIONS: Results highlighted the therapeutic potential of PBA in diabetes muscle wastage.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Fenilbutiratos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Injeções Intraperitoneais , Masculino , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Fenilbutiratos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estreptozocina
17.
Ren Fail ; 41(1): 267-277, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30982374

RESUMO

OBJECTIVE: To compare the anti-peritoneal fibrotic effects between a mammalian target of rapamycin complex 1-specific blocker and a phosphatidyl-inositol 3-kinase/mammalian target of rapamycin dual-blocker. METHODS: A total of 40 male Sprague-Dawley rats were randomly divided into five groups with eight animals per group. The normal group (N group) did not receive any intervention. The normal saline group (NS group) received an intraperitoneal injection of normal saline at 1 ml/100 g daily. The model group (3 W group), rapamycin (RAPA) group and BEZ235 (PI3K/mTOR dual-blocker) group all received an intraperitoneal injection of 0.1% chlorhexidine gluconate at 1 ml/100g daily. And the RAPA and BEZ235 groups also received a 0.5 mg/d RAPA or 2.5 mg/d BEZ235 gavage every day, respectively. Rats in each group were sacrificed after 3 weeks. RESULTS: Immunohistochemistry, real-time PCR and western blotting analysis of fibrosis-related indicators (FN, Col 1, and α-SMA) confirmed that RAPA and BEZ235 significantly inhibited peritoneal fibrosis and that these two drugs had similar effects. The p-Akt, p-mTOR, p-p70S6K expression levels were significantly up-regulated in the 3 W group compared to the NS group, confirming that the mTOR pathway was significantly activated during peritoneal fibrosis. RAPA significantly inhibited the phosphorylation of mTOR and p70S6K but did not have significant effects on p-Akt upstream of mTOR. BEZ235 had significant inhibitory effects on all signaling molecules (p-Akt, p-mTOR, and p-p70S6K) in the mTOR pathway. CONCLUSION: RAPA did not up-regulate p-Akt in a negative feedback fashion. Both drugs effectively inhibited peritoneal fibrosis.


Assuntos
Imidazóis/farmacologia , Falência Renal Crônica/terapia , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/prevenção & controle , Quinolinas/farmacologia , Sirolimo/farmacologia , Animais , Clorexidina/administração & dosagem , Clorexidina/análogos & derivados , Clorexidina/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/uso terapêutico , Injeções Intraperitoneais , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/patologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
18.
Recent Pat Biotechnol ; 13(2): 137-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973107

RESUMO

BACKGROUND: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. OBJECTIVE: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. METHOD: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. RESULTS: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. CONCLUSION: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.


Assuntos
Analgésicos Opioides/farmacologia , Antioxidantes/farmacologia , Tolerância a Medicamentos/genética , Genes fos , Morfina/farmacologia , Dor/tratamento farmacológico , alfa-Tocoferol/farmacologia , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Dor/genética , Dor/metabolismo , Dor/fisiopatologia , Patentes como Assunto , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
19.
Biomed Environ Sci ; 32(3): 153-161, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30987689

RESUMO

OBJECTIVE: This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. METHODS: Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 µL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. RESULTS: CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. CONCLUSION: These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.


Assuntos
Hepcidinas/farmacologia , Interleucina-6/farmacologia , Ferro/metabolismo , Cirrose Hepática/terapia , Transferrina/metabolismo , Animais , Análise Química do Sangue , Tetracloreto de Carbono/toxicidade , Injeções Intraperitoneais , Ferro/sangue , Leucocitose/induzido quimicamente , Leucocitose/terapia , Cirrose Hepática/induzido quimicamente , Masculino , Ratos , Tioacetamida/toxicidade , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia
20.
Cell Prolif ; 52(3): e12608, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30932251

RESUMO

OBJECTIVES: We performed histological, cellular and behavioural analyses of the effects of cyclophosphamide (CTX), a chemotherapeutic drug, in the developing cerebellum and aimed to provide valuable insights into clinical application of CTX in children. MATERIALS AND METHODS: C57BL/6 mice and Math1-dependent GFP expression transgenic mice were used in the research. H&E staining was performed to analyse histological effects of CTX in the cerebellum. Staining for EdU and TUNEL was used to estimate the cell proliferation and apoptosis. Rotarod test and hanging wire test were used to evaluate the behavioural functions. Immunofluorescent staining was used to identify the cell types. The differentiation markers and genes related to Sonic Hedgehog (SHH) signalling were measured via quantitative real-time PCR or immunoblotting. RESULTS: We found that while CTX induced a significant reduction in cell proliferation and increased apoptosis in the EGL in 48 hours, the behavioural functions and the multilayer laminar structure of cerebella were largely restored when the mice grew to adults. Mechanistically, granule neuron progenitors, driven by the SHH signalling, enhanced the capability of proliferation quickly after CTX administration was stopped, which allowed the developing cerebellum to catch up and to gradually replenish the injury. CONCLUSION: The chemotherapeutic agent CTX induces an immediate damage to the developing cerebellum, but the cerebellar multilayer laminar structure and motor function can be largely restored if the agent is stopped shortly after use.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Animais , Animais Recém-Nascidos , Antineoplásicos Alquilantes/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Criança , Ciclofosfamida/administração & dosagem , Proteínas Hedgehog/metabolismo , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Neurogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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