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1.
Zhonghua Er Ke Za Zhi ; 58(1): 30-34, 2020 Jan 02.
Artigo em Chinês | MEDLINE | ID: mdl-31905473

RESUMO

Objective: To investigate the impact of hypoxic-ischemic brain injury (HIBI) on brain development in neonatal rats of different sexes. Methods: From January 1 to December 31, 2018, 60 7-day-old SD rats were randomly divided into HIBI-F group (20 rats), HIBI-M group (20 rats), and control group (20 rats, 10 females and 10 males). The animal model of HIBI was established with Rice-Vannucci method, with the rats' left common carotid artery double-ligated and severed. The rats were then placed in an incubator and exposed to a hypoxic gas mixture (8% O(2), 92% N(2)) for 90 minutes. No intervention was given to the control group. Two weeks after HIBI, the motor development was evaluated by footprint analysis, the residual brain volume was measured by brain magnetic resonance imaging (MRI), and the damage of synaptic ultra structure was analyzed by transmission electron microscope. One-way ANOVA or χ(2) test was used for inter-group statistical analysis, and paired sample t test was used to compare the bilateral step length and toe distance of rats in the same group. Results: The mortality rate of HIBI-F was significantly higher than that of HIBI-M (20%(4/20) vs. 10%(2/20), χ(2)=40.000, P=0.001). The right step length and toe distance in HIBI-M group and HIBI-F group were significantly shorter than those in control group ((7.5±0.3) cm and (7.9±0.5) cm vs. (8.2±0.5) cm, F=9.605, P<0.01, (0.9±0.1) cm and (1.0±0.0) cm vs. (1.1±0.1) cm, F=71.437, P<0.01). Besides, according to above data, the right step length and toe distance in HIBI-M group were significantly shorter than those in the HIBI-F group (both P<0.01). Furthermore, the right step length was significantly shorter than the left step length ((8.3±0.4) and (8.3±0.5) cm, t=5.289 and 10.580, P=0.001 and 0.010, respectively) and toe distance ((1.1±0.1) and (1.1±0.1) cm, t=7.953 and 6.435, respectively, both P<0.01) in both HIBI-M group and HIBI-F group. Similarly, the synaptic gap of the left precentral gyrus neurons was longer in HIBI-M group and HIBI-F group than that in control group ((23.4±1.3) and (19.7±1.6) nm vs. (18.9±0.6) nm, F=71.719, P<0.01), and also longer in HIBI-M group than that in HIBI-F group (t=7.645, P<0.01). Likewise, the residual brain volume in HIBI-M group and HIBI-F group was significantly less than that in control group ((67±4)% and (75±5)% vs. 100%, F=406.122, P<0.01), and the residual brain volume in HIBI-M group was significantly less than that in HIBI-F group (t=-5.281, P<0.01). Conclusions: Male neonatal rats are more vulnerable to HIBI and have severer subsequent brain injury and hemiplegia. Different treatment strategies for HIBI patients of different sexes should be developed.


Assuntos
Hipóxia-Isquemia Encefálica , Animais , Animais Recém-Nascidos , Encéfalo , Modelos Animais de Doenças , Feminino , Humanos , Hipóxia-Isquemia Encefálica/mortalidade , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
2.
Zhonghua Yi Xue Za Zhi ; 100(2): 141-145, 2020 Jan 14.
Artigo em Chinês | MEDLINE | ID: mdl-31937055

RESUMO

Objective: To observe the effect of autophagy of tibial growth plate chondrocyte on apoptosis in chronic renal insufficiency (CRI) rats. Methods: Male 4-week-old SD rats were randomly divided into two groups: (1) Sham group: only the left ureter was exposed (n=10); (2) CRI group: the left ureter was ligated to cause CRI (n=10). The urine from all the rats was collected 6 weeks after the operation and the total protein content was measured. Then all the rats were sacrificed and the concentrations of creatinine and urea nitrogen in intracardiac blood were detected. The proximal tibia were fixed and decalcified to prepare histological sections, and the number of chondrocytes of column cells in the proliferative area of tibia growth plate was observed by saffron O staining. The expression rate of protein Light Chain-3, an autophagy marker of chondrocytes, was detected by immunofluorescence. The apoptosis rate of chondrocytes was detected by the method of TUNEL assay. The level of glycogenin-1, a glycogen formation marker of chondrocyte was detected by immunohistochemistry in chondrocytes. Results: The 24 h urine total protein was higher in CRI group [(163.5±11.3) mg vs (38.6±9.8) mg, t=25.620, P<0.001]. The levels of blood creatinine [(67.3±16.2) µmol/L vs (28.4±11.5) µmol/L, t=5.974, P<0.001] and urea nitrogen [(16.4±6.4) mmol/L vs (4.8±2.0) mmol/L, t=5.198, P<0.001] were higher in CRI group. The number of chondrocytes of column cells in the proliferating area of tibia growth plate was lower in CRI group (4.2±2.1 vs 9.1±3.8, t=3.109, P=0.006). The expression rate of LC-3 protein in chondrocytes of CRI group was lower [(27.2±12.6)% vs (51.4±18.2)%, t=3.457, P=0.003]. The level of glycogenin-1 of chondrocytes in CRI group increased significantly (6.1±2.5 vs 3.5±1.8, t=2.669, P=0.016). The apoptosis rate of chondrocytes in CRI group also increased [(17.2±4.8)% vs (5.1±3.4)%, t=6.505, P<0.001]. Conclusion: Malfunction of autophagy in tibial growth plate chondrocytes causes increased apoptosis rate in CRI rats, which might be caused by the failure of glycogen degradation in chondrocytes.


Assuntos
Autofagia , Insuficiência Renal Crônica , Animais , Apoptose , Condrócitos , Lâmina de Crescimento , Masculino , Ratos , Ratos Sprague-Dawley , Tíbia
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 58-64, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31948526

RESUMO

OBJECTIVE: To study the effect and mechanism of action of irisin on hypoxic-ischemic brain damage in neonatal rats. METHODS: A total of 248 7-day-old Sprague-Dawley rats were randomly divided into a sham-operation group, a model group, and low- and high-dose irisin intervention groups (n=62 each). The rats in the model and irisin intervention groups were given hypoxic treatment after right common carotid artery ligation to establish a model of hypoxic-ischemic brain damage. Those in the sham-operation group were given the separation of the right common carotid artery without ligation or hypoxic treatment. The rats in the high- and low-dose irisin intervention groups were given intracerebroventricular injection of recombinant irisin polypeptide at a dose of 0.30 µg and 0.15 µg respectively. Those in the model and sham-operation groups were given the injection of an equal volume of PBS. The water maze test was used to compare neurological behaviors between groups. TTC staining, hematoxylin-eosin staining and TUNEL staining were used to observe histopathological changes of the brain. Western blot was used to measure the expression of the apoptosis-related molecules cleaved-caspase-3 (CC3), BCL-2 and BAX. RESULTS: Compared with the sham-operation group, the model group had a significant increase in latency time and a significant reduction in the number of platform crossings (P<0.05). Compared with the model group, the high-dose irisin intervention group had a significant reduction in latency time and a significant increase in the number of platform crossings (P<0.05). Compared with the sham-operation group, the model group had massive infarction in the right hemisphere, with significant increases in karyopyknosis and karyorrhexis. Compared with the model group, the high-dose irisin intervention group had a smaller infarct area of the right hemisphere, with reductions in karyopyknosis and karyorrhexis. The model group had a significantly higher apoptosis rate of cells in the right cerebral cortex and the hippocampus than the sham-operation group. The high-dose irisin intervention group had a significantly lower apoptosis rate than the model group (P<0.05). At 24 and 48 hours after modeling, the sham-operation group had a significantly lower level of CC3 than the model group (P<0.05). Compared with the model group, the high-dose irisin intervention group had a significantly lower level of CC3 and a significantly higher BCL-2/BAX ratio (P<0.05). The low-dose irisin intervention group had similar laboratory markers and histopathological changes of the brain to the model group. CONCLUSIONS: Irisin can alleviate hypoxic-ischemic brain damage in neonatal rats in a dose-dependent manner, possibly by reducing cell apoptosis in the cerebral cortex and the hippocampus.


Assuntos
Hipóxia-Isquemia Encefálica , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo , Ratos , Ratos Sprague-Dawley
4.
Orthod Craniofac Res ; 23(1): 44-49, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31461554

RESUMO

OBJECTIVE: This study aimed to explore the role of miR-140-5p in cranial base synchondrosis chondrocytes (CBSCs) under cyclic tensile strain (CTS). SETTING AND SAMPLE POPULATION: A total of 25 1-week-old Sprague Dawley rats from Shanghai Laboratory Animal Center, Chinese Academy of Sciences, were used. MATERIAL AND METHODS: The second passage of CBSCs was applied with CTS at 10% elongation (1 Hz) for 24 hours. MiR-140-5p levels in CBSCs were detected by qRT-PCR. The role of miR-140-5p in CBSCs was evaluated by transfection of mimics and inhibitor. RNA sequencing and online search of miRNA databases (TargetScan, miRDB and miRanda) were used in prediction of miR-140-5p targets. A luciferase reporter assay was applied to identify the target gene of miR-140-5p. RESULTS: Compared with the control, the expression of Col2a1 and Sox9 was significantly higher after CTS (P < .05). Also, CBSCs demonstrated higher expression of miR-140-5p after CTS loading for 24 hours (P < .05). Overexpression of miR-140-5p promoted ECM synthesis under CTS loading environment, while suppression of miR-140-5p inhibited the effect. Bloc1s2 was a putative target gene of miR-140-5p. CONCLUSIONS: The expression of ECM in CBSCs could be promoted by CTS and miR-140-5p might play a role in this process through targeting Bloc1s2.


Assuntos
Condrócitos , MicroRNAs , Animais , China , Ratos , Ratos Sprague-Dawley , Base do Crânio
5.
Orthod Craniofac Res ; 23(1): 35-43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31593373

RESUMO

OBJECTIVE: The goal of this study was to investigate potential negative sequelae of orthodontic force application ±delivery of an osteoclast inhibitor, recombinant osteoprotegerin protein (OPG-Fc), on periodontal tissues. SETTING AND SAMPLE POPULATION: Sprague Dawley rats from a commercial supplier were investigated in a laboratory setting. MATERIALS AND METHODS: Rats were randomly divided into four groups (n = 7 each): one group with no orthodontic appliances and injected once prior to the experimental period with empty polymer microspheres, one group with orthodontic appliances and injected once with empty microspheres, one group with orthodontic appliances and injected once with polymer microspheres containing 1 mg/kg of OPG-Fc, and one group with orthodontic appliances and injected with non-encapsulated 5 mg/kg of OPG-Fc every 3 days during the experimental period. The animals were euthanized after 28 days of tooth movement for histomorphometric analyses. RESULTS: Root resorption, PDL area and widths were similar in animals without appliances and animals with appliances plus high-dose OPG-Fc. PDL blood vessels were compressed and decreased in number in all animals that received orthodontic appliances, regardless of OPG-Fc. Hyalinization was significantly increased only in animals with orthodontic appliances plus multiple injections of 5 mg/kg non-encapsulated OPG-Fc when compared to animals without appliances. CONCLUSIONS: Results of this study indicate that while pharmacological modulation of tooth movement through osteoclast inhibition is feasible when delivered in a locally controlled low-dose manner, high-dose levels that completely prevent tooth movement through bone may decrease local blood flow and increase the incidence of hyalinization.


Assuntos
Reabsorção da Raiz , Técnicas de Movimentação Dentária , Animais , Osteoclastos , Ligamento Periodontal , Ratos , Ratos Sprague-Dawley , Raiz Dentária
6.
Toxicol Lett ; 319: 40-48, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706004

RESUMO

Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague-Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.


Assuntos
Cardiotoxinas/toxicidade , Alucinógenos/toxicidade , Animais , Células CHO , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Canal de Potássio ERG1/metabolismo , Eletrocardiografia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/toxicidade , Ratos , Ratos Sprague-Dawley , Quinases Ativadas por p21/biossíntese , Quinases Ativadas por p21/genética
7.
Toxicol Lett ; 319: 1-10, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689472

RESUMO

Chlorocholine chloride (CCC), a plant growth retardant, may act as an endocrine disruptor. Our previous study showed that pubertal CCC exposure in rats might decrease testosterone (T) synthesis. This study observed the changes in pubertal development and reproduction of male rats exposed to CCC and its underlying mechanisms. Rats were exposed to CCC (0, 75, 137.5 and 200 mg/kg bw/day) from postnatal day 23 to 60. The results showed that CCC treatment delayed the onset of puberty and reduced the relative organ weight of prostate. Seminiferous tubules with deciduous spermatogenic cells were observed in the 200 mg/kg bw/day group. Sexual behavior was inhibited in the 137.5 and 200 mg/kg bw/day groups. Sperm motility, litter size and normalized anogenital distance (AGD) of male pups were decreased in the 137.5 and 200 mg/kg bw/day groups. Serum kisspeptin level and serum and testicular levels of T were reduced in all CCC treated groups. Crucial hormones in hypothalamic-pituitary-testicular (HPT) axis were reduced subsequently after CCC treatment. Collectively, our results demonstrated that CCC might disturb HPT axis through suppressing the secretion of kisspeptin and subsequently lead to delayed puberty onset and impaired reproductive functions.


Assuntos
Clormequat/toxicidade , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Genitália/anatomia & histologia , Genitália/efeitos dos fármacos , Genitália/crescimento & desenvolvimento , Hormônios Esteroides Gonadais/sangue , Kisspeptinas/metabolismo , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testosterona/sangue
8.
Life Sci ; 240: 117085, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759042

RESUMO

AIMS: Our study was designed to explore the function and mechanism of Tanshinone IIA in alleviating pain syndrome caused by endometriosis (EMs). MAIN METHODS: Female Sprague-Dawley rats went through autotransplantation operation to establish EMs model. The rats were randomly divided into five groups: sham, model, positive, Tanshinone IIA (L) (3 mg/kg/d) and Tanshinone IIA (H) (12 mg/kg/d) group. Volume of ectopic endometrium was measured after 21 days of continuous administration. Serum estradiol (E2) was detected by enzyme linked immunosorbent assay (Elisa). The protein expression of angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), angiotensin II (ANGII) and angiotensin II type 2 receptor (AT2) in the dorsal root ganglion (DRG) neurons were measured by immunohistochemistry and Western Blotting. The mRNA expression levels of AGT and ANGII were measured by Real-time polymerase chain reaction (PCR). KEY FINDINGS: Tissue measurements showed that tanshinone IIA significantly inhibited the growth of ectopic endometrium. Tanshinone IIA could improve the paw withdrawal threshold thus reducing the mechanical hyperalgesia of EMs rats. Moreover, Tanshinone IIA regulated the DRG renin angiotensin system (RAS) by reducing the protein expression of AGT, REN, ACE, ANGII and AT2 in DRG neurons. Furthermore, Real-time PCR results also showed that the mRNA expression levels of AGT and ANGII in the DRG neurons were decreased. SIGNIFICANCE: The Tanshinone IIA inhibitory effect on the EMs associated pain in EMs rats might occur through decreasing the expression of E2, ANGII and AT2, thus halting DRG sprouting and promoting hyperalgesia threshold.


Assuntos
/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios/patologia , Endometriose/tratamento farmacológico , Gânglios Espinais/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Endometriose/patologia , Estradiol/metabolismo , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Ratos , Ratos Sprague-Dawley
9.
Toxicol Lett ; 319: 204-212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760061

RESUMO

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/urina , Metaboloma/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
10.
Toxicol Lett ; 320: 95-102, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760062

RESUMO

Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that "Axon" and "Neurotrophin Signaling Pathway" was the top significant GO term and pathway, respectively. 7 miRNAs both related to "Axon" and "Neurotrophin Signaling Pathway" were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3ß, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.


Assuntos
Axônios/efeitos dos fármacos , Hexanonas/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , Nervo Isquiático/efeitos dos fármacos , Solventes/toxicidade , Medula Espinal/efeitos dos fármacos , Animais , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Transcriptoma
11.
Toxicol Lett ; 319: 225-236, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760063

RESUMO

N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76 %) and feces (11-15 %) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25 % of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14 % and 8 % of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83 %; feces, 14 %) and male (urine, 69 %; feces, 11 %) and female (urine, 72 %; feces, 9 %) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.


Assuntos
Hepatócitos/metabolismo , Plastificantes/farmacocinética , Sulfonamidas/farmacocinética , Administração Intravenosa , Animais , Bile/metabolismo , Células Cultivadas , Fezes/química , Feminino , Humanos , Intubação Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos , Plastificantes/metabolismo , Plastificantes/toxicidade , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/metabolismo , Distribuição Tecidual
12.
Life Sci ; 240: 117096, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760097

RESUMO

Aim Liver fibrosis represents a massive global health burden with limited therapeutic options. Thus, the need for curative options is evident. Thus, this study aimed to assess the potential antifibrotic effect of honokiol in Concanavalin A (Con A) induced immunological model of liver fibrosis as well the possible underlying molecular mechanisms. METHODS: Male Sprague-Dawley rats were treated with either Con A (20 mg/kg, IV) and/or honokiol (10 mg/kg, orally) for 4 weeks. Hepatotoxicity indices were as well as histopathological evaluation was done. Hepatic fibrosis was assessed by measuring alpha smooth muscle actin (α-SMA) expression and collagen fibers deposition by Masson's trichrome stain and hydroxyproline content. To elucidate the underlying molecular mechanisms, the effect of honokiol on oxidative stress, inflammatory markers as well as transforming growth factor beta (TGF-ß)/SMAD and mitogen-activated protein kinase (MAPK) pathways was assessed. KEY FINDINGS: Honokiol effectively reversed the hepatotoxicity indices elevations and abnormal histopathological changes induced by Con A. Besides, honokiol attenuated Con A-induced liver fibrosis by down-regulation of hydroxyproline levels, α-SMA expression together with a marked decrease in collagen fibers deposition. Mechanistically Con A induced oxidative stress, provocation of inflammatory responses and activation of TGF-ß/SMAD/MAPK pathways. Contrariwise, honokiol co-treatment significantly restored antioxidant defence mechanisms, down-regulated inflammatory cascades and inhibited TGF-ß/SMAD/MAPK signaling pathways. CONCLUSION: The results provide an evidence for the promising antifibrotic effect of honokiol that could be partially due to suppressing oxidative stress and inflammatory processes as well as inhibition of TGF-ß/SMAD/MAPK signaling pathways.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Cirrose Hepática/prevenção & controle , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Actinas/metabolismo , Animais , Concanavalina A , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida
13.
Fitoterapia ; 140: 104447, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31805306

RESUMO

According to the basic theories of traditional Chinese medicine, Gastrodia elata (GE) is clinically utilized for the treatment of cephalalgia and migraine. The gastrodigenin (p-hydroxybenzyl alcohol, HBA), one of the effective components of GE, may pass through the blood-brain barrier (BBB) to exert its pharmacological effects. This study aimed to investigate BBB permeability of HBA via in vitro hCMEC/D3 BBB model and in vivo microdialysis in rats. For the establishment of in vitro BBB model, hCMEC/D3 cells were used to construct the monolayer. The integrity of the monolayer was evaluated by TEER measurements, expression analysis of tight junction proteins (claudin-5, zo-1 and occludin) and apparent permeability coefficients (Papp) of fluorescein disodium. During the 6-day incubation of hCMEC/D3 cells, the values of TEER gradually increased and maintained above 100 Ω·cm2. Besides, the expression levels of claudin-5 and zo-1 in hCMEC/D3 cells increased over time, and tended to be stable, suggesting that integrity of the monolayer has been completely established. Moreover, the Papp of fluorescein disodium was 3.94 × 10-7 cm·s-1 after administration for 180 min, indicating that the monolayer retains the characteristics of BBB and can restrict the diffusion of hydrophilic small-molecule compounds. A sensitive HPLC method was established for HBA detection, and the transport rate of HBA was assessed by a transwell system. HBA crossed the hCMEC/D3 BBB model rapidly, but a plateau was observed when HBA concentrations were relatively similar between the two sides of transwell. Permeability assay revealed that 32.91% of HBA could penetrate the in vitro BBB model after 240 min of administration. In vivo BBB permeability was evaluated by determining the concentrations of HBA in blood and brain simultaneously. Following HBA administration, the samples of microdialysis were collected at 20, 40 and 60 min, and then every 30 min until the procedure ended. Pharmacokinetic parameters of HBA showed that HBA could pass through BBB and reach its maximum concentration at 40 min in blood and brain tissue. Furthermore, AUC0-t and AUC0-inf for the brain-to-blood distribution ratio of HBA were 0.1925 and 0.2083, respectively, indicating that approximately 20% of HBA in blood could pass through the BBB and subsequently transported into the brain. Both in vitro and in vivo experiments confirmed that HBA could penetrate the BBB. In summary, the findings of this study highlight that a promising amount of HBA in blood can pass through the BBB and exerts its pharmacological effects on central nervous system (CNS) diseases.


Assuntos
Álcoois Benzílicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Animais , Transporte Biológico , Linhagem Celular , Humanos , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley
14.
Gene ; 728: 144279, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31821871

RESUMO

AIM OF THE STUDY: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease. Qi Teng Xiao Zhuo granules have been proposed as a prescription of traditional Chinese medicine (TCM) for treatment of CGN, however,the comprehensive molecular mechanism underlying this therapeutic effectremains unclear to date. Our study aimed to evaluate and analyze the possible roles and molecular mechanisms of Qi Teng Xiao Zhuo granule-mediated treatment of CGN induced by adriamycin in rats. MATERIALS AND METHODS: RNA-sequencing and real-time polymerase chain reaction (RT-PCR) were applied to identify specifically expressed long noncoding RNAs (lncRNAs) in glomerular tissues of rats from the control group, adriamycin-induced group, and Qi Teng Xiao Zhuo granules group (n = 3). Differentially expressed lncRNAs and mRNAs (messengerRNAs) were screened out among the 3 groups. Gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for mRNAs. LncRNA-mRNA co-expression network was constructed to analyse for the genes. The protein-protein interaction (PPI) network was visualized. RESULTS: A total of 473 significantly up and down-regulated lncRNAs, 753 up and down-regulated mRNAs were identified. Additionally, it is worth noting that TOP2a (topoisomerase (DNA) II alpha), with the highest connectivity degree in PPI network, was enriched in variouskinds of pathways. Coding-non-coding gene co-expression networks (CNC network) were drawn based on the correlation analysis between lncRNAs and mRNAs. Ten lncRNAs, NONRATT009275.2, NONRATT025409.2, NONRATT025419.2, MSTRG.7681.1, ENSRNOT00000084373, NONRATT000512.2, NONRATT006734.2, ENSRNOT00000084386, NONRATT021738.2, ENSRNOT00000084080, were selected to analyse the relationship between LncRNAs and Qi Teng Xiao Zhuo granules via the CNC network (Coding-non-coding gene co-expression networks) and GO analysis. Real-time PCR results confirmed that the six lncRNAs were specifically expressed in the Qi Teng Xiao Zhuo granules rats. CONCLUSIONS: The ten lncRNAs might play important roles in the Qi Teng Xiao Zhuo granules treatment of CGN. Key genes, such as Ptprc (protein tyrosine phosphatase, receptor type, C), TOP2a, Fos (FBJ osteosarcoma oncogene), Myc (myelocytomatosis oncogene), etc, may be crucial biomarkers for Qi Teng Xiao Zhuo granules.


Assuntos
Biomarcadores/análise , Medicamentos de Ervas Chinesas/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite/genética , RNA Longo não Codificante/genética , Animais , Doença Crônica , Glomerulonefrite/tratamento farmacológico , Masculino , Mapas de Interação de Proteínas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Toxicol Lett ; 320: 19-27, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778773

RESUMO

The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 ß-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.


Assuntos
Anilidas/farmacologia , Benzoquinonas/farmacologia , Dexametasona/toxicidade , Glucocorticoides/toxicidade , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Acetilação , Animais , Linhagem Celular , Proteínas de Choque Térmico HSP90/metabolismo , Desacetilase 6 de Histona/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Ratos Sprague-Dawley , Via Secretória , Técnicas de Cultura de Tecidos
16.
Toxicol Lett ; 319: 160-167, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734271

RESUMO

Overexposure to 1,2-dichloroethane (1,2-DCE) can induce brain edema, but the underlying mechanisms remain largely unknown. Aquaporin 4 (AQP4) is the most prevalent water channel in the brain, and the pool of AQP4 facilitates brain edema by controlling the inflow and clearance of brain water. MicroRNAs play an important role in the regulation of brain edema via RNA silencing and post-transcriptional regulation of gene expression. To explore the regulation role of AQP4 and microRNA in 1,2-DCE-induced brain edema, Sprague-Dawley (SD) rats and AQP4 knockout CD-1 mice were exposed to 1,2-DCE by inhalation for 7 days (0, 600, 1,800 mg/m3) and 28 days (0, 100, 350, 700 mg/m3), respectively. The results showed that 1,2-DCE induces brain edema, in both rats and mice, characterized by an increase in brain water content and vacuolations in the brain parenchyma and around the vessels of the cerebral cortex. Notably, 1,2-DCE exposure can down-regulate AQP4 expression, in both rats and mice. Also, deleting AQP4 intensifies 1,2-DCE-induced brain edema in mice. Meanwhile, microRNA-29b-3p (miR-29b) expression increases with 1,2-DCE exposure, in both rats and mice. A negative correlation was found between the expression of miR-29b and AQP4 in vivo. Moreover, the negative regulation of miR-29b by direct targeting to AQP4 was confirmed by dual luciferase reporter assay in vitro. Taken together, our findings indicate that AQP4 plays an important role in balancing water content in 1,2-DCE-induced brain edema. The dysregulation of miR-29b after 1,2-DCE exposure can aggravate brain edema by directly suppressing the expression of AQP4.


Assuntos
Aquaporina 4/efeitos dos fármacos , Edema Encefálico/induzido quimicamente , Dicloretos de Etileno/toxicidade , MicroRNAs/genética , Administração por Inalação , Animais , Aquaporina 4/genética , Água Corporal/metabolismo , Química Encefálica/efeitos dos fármacos , Edema Encefálico/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/biossíntese , Ratos , Ratos Sprague-Dawley
17.
Arch Oral Biol ; 109: 104570, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31568992

RESUMO

OBJECTIVE: The aim of this study is to investigate the effects of 17ß-Estradiol (E2) at different concentrations combined with cyclical compressive stress on the proliferation and differentiation of mandibular condylar chondrocytes (MCCs). DESIGN: MCCs, isolated from female Sprague-Dawley rats, were exposed to E2 at different concentration, cyclical compressive stress or the combination, effects of which on MCCs proliferation and differentiation were detected. RESULTS: E2 at physiological concentration (10-9 mol/L) has lower proliferative effects on MCCs, compared with non-physiological concentration (10-12 mol/L or 10-6 mol/L). For MCCs differentiation, effects of E2 at different concentration are totally opposite: E2 at 10-9 mol/L promotes MCCs differentiation, but at 10-12 mol/L or 10-6 mol/L, it inhibits MCCs differentiation. When combined with E2 at 10-9 mol/L, cyclical compressive stress shows synergistic effect on proliferation and differentiation. However, when combined with E2 at 10-12 mol/L or 10-6 mol/L cyclical compressive stress reverses the inhibition in MCCs differentiation provoked by E2 at 10-12 mol/L or 10-6 mol/L. CONCLUSION: Effects of E2 combined with cyclical compressive stress on MCCs proliferation and differentiation are different, which suggests that orthodontist should take fully consideration of the levels of E2 and adopt comprehensive strategies, so as to achieve better orthodontic effect.


Assuntos
Condrócitos/citologia , Estradiol/farmacologia , Côndilo Mandibular/citologia , Pressão , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Ratos , Ratos Sprague-Dawley
18.
Arch Oral Biol ; 109: 104529, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31574324

RESUMO

OBJECTIVE: Periodontitis disease is a chronic inflammation, and the prevention or treatment of periodontal disease is important for improving oral health and averting systemic diseases.Acer tegmentosum Maxim (ATM) is a type of deciduous tree in Korea. ATM extracts have been traditionally used to treat various dieases. This study investigated the effects of ATM extract on mitigation of periodontitis in vitro and in vivo. DESIGN: The current study investigated whether extracts ofAcer tegmentosum Maxim (ATM) attenuated periodontitis induced by Porphyromonas gingivalis-derived lipopolysaccharide (LPS) in vitro and in vivo. We used a rat model of experimental periodontitis that received oral administration of 1 mg/kg P. gingivalis-derived LPS for 10 days. Periodontitis models was treated with two different dosages of ATM (30 or 100 mg/kg) during the same period of periodontal induction for histological analysis. RESULTS: The results indicated that aqueous ATM extracts effectively ameliorated ligature-induced periodontitis through of the antibacterial, anti-oxidative, and anti-inflammatory activities. CONCLUSION: These pre-clinical results suggest the need for further studies on the anti-periodontitis effect of ATM in humans. Thus, ATM could be used as a natural anti-periodontitis agent for the treatment of periodontitis.


Assuntos
Acer/química , Periodontite/tratamento farmacológico , Extratos Vegetais/farmacologia , Porphyromonas gingivalis/patogenicidade , Animais , Linhagem Celular , Humanos , Lipopolissacarídeos , Masculino , Malondialdeído/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Periodontite/microbiologia , Casca de Planta/química , Ratos , Ratos Sprague-Dawley , República da Coreia
19.
Biosci Biotechnol Biochem ; 84(1): 171-177, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31476130

RESUMO

We tested the hypothesis that α-lactalbumin inhibits the disruption of intestinal barrier function and liver cirrhosis by restoring gut-liver axis function in thioacetamide (TAA) -treated rats. Rat diets were supplemented with α-lactalbumin replacing 50% of dietary protein. After consuming α-lactalbumin for one week, rats were intraperitoneally injected with TAA twice a week for 14 weeks. The α-lactalbumin-enriched diet significantly inhibited the elevation of plasma alanine aminotransferase, aspartate aminotransferase, and hyaluronic acids. The supplement significantly reduced plasma lipopolysaccharide levels and increased occludin mRNA level. Hepatic fibrosis and regenerative nodules was developed and intestinal villi were shortened by TAA; α-Lactalbumin attenuated these histopathological changes. These results indicated that α-lactalbumin improved intestinal barrier function, suppressing endotoxin levels. These data also suggested that α-lactalbumin ameliorated the impairment of the gut-liver axis by TAA, inhibiting the development of liver cirrhosis.


Assuntos
Suplementos Nutricionais , Trato Gastrointestinal/efeitos dos fármacos , Lactalbumina/uso terapêutico , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/dietoterapia , Fígado/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Tioacetamida/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Fibrose/tratamento farmacológico , Trato Gastrointestinal/metabolismo , Expressão Gênica/efeitos dos fármacos , Ácido Hialurônico/sangue , Injeções Intraperitoneais , Lipopolissacarídeos/sangue , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/prevenção & controle , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Tioacetamida/administração & dosagem , Proteínas de Junções Íntimas/genética
20.
Biosci Biotechnol Biochem ; 84(1): 159-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31483212

RESUMO

We tested whether Sake Lees (SL) had inhibitory effects on hyperalgesia in the hindpaw under psychophysical stress conditions. Male rats were subjected to repeated forced swim stress treatments (FST) from Day -3 to Day -1. Intraperiotoneal administration of SL which contained low concentration of ethanol (SLX) was conducted after each FST. On Day 0, formalin-evoked licking behaviors and Fos responses in the lumbar spinal cord (DH) and several areas within the rostral ventromedial medulla (RVM) were quantified as nociceptive responses. FST-induced hyperalgesia in the hindpaw was prevented by repeated SL and SLX treatments. Fos expression was significantly increased in DH and some areas within the RVM under FST, which was prevented by repeated SL or SLX. These findings indicated that daily administration of SL had the potential to alleviate stress-induced hyperalgesia.


Assuntos
Fermentação , Membro Posterior/metabolismo , Hiperalgesia/tratamento farmacológico , Oryza/química , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Estresse Fisiológico/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Etanol/química , Formaldeído/administração & dosagem , Formaldeído/farmacologia , Hiperalgesia/etiologia , Imuno-Histoquímica , Masculino , Manejo da Dor , Medição da Dor , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/imunologia , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Serotonina/imunologia , Serotonina/metabolismo , Natação/fisiologia , Distribuição Tecidual
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