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1.
Wei Sheng Yan Jiu ; 49(5): 790-794, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070826

RESUMO

OBJECTIVE: To explore the effect of myrica flavone on male reproductive toxicity induced by cyclophosphamide and its mechanism. METHODS: Thirty 6-week-old male ICR mice were randomly divided into 5 groups: blank control group, cyclophosphamide reproductive injury model group, myricetin low-medium high-dose intervention group. Except the blank control group, the other groups were intraperitoneally injected with cyclophosphamide 50 mg/kg daily for 7 consecutive days. The myricetin group received intragastric administration of 100, 200, and 400 mg/kg myricetin daily for 30 consecutive days since the second day of modeling. The blank control group and the model control group were given an equal volume of a 0. 25% sodium carboxymethyl cellulose solution. The body weight was measured every 3 days, and the day after the last administration, the mice were sacrificed by cervical dislocation, and the epididymis and testes were quickly taken. Testicular weighing, testicular index calculation, epididymis to obtain sperm, sperm analyzer to analyze sperm density and vitality. The expression of Bax and Bcl-2 in testicular tissues was detected by immunoblotting, and the mitochondrial membrane potential of sperm was detected by flow cytometry. RESULTS: After 9 days of modeling, the weight of mice in the model group was lower than that of the blank control group, which was statistically different(P<0. 05). There was no difference between the myricetin treatment group and the model group. The testis index of the model group was(3. 93±0. 91)mg/g, which was significantly lower than that of the blank control group(6. 93±0. 98)mg/g, and the difference was statistically significant(P<0. 05). After treatment with bayberry flavonoids, the testis index increased, in the 100 and 200 groups and 400 mg/kg testis index were(3. 94±1. 21) mg/g, (4. 33±0. 88) mg/g, and(4. 80±0. 43) mg/g, respectively. Compared with model control group, The difference was statistically significant(P<0. 05 and P<0. 01). Compared with the control group, the sperm density, sperm rate of forward movement, sperm rate of non-forward movement, and decreased sperm rate of non-moving sperm increased in the model group. After treatment with bayberry flavonoids, compared with the model group, the sperm density, sperm rate of forward motion, and sperm rate of non-forward motion increased, and the immobility sperm rate decreased. The 200 and 400 mg/kg groups had statistical significance(P<0. 05 or P<0. 01); the normal rate of sperm mitochondrial membrane potential in the model group was(54. 70±5. 45)%, and the normal mitochondrial membrane potential rate after treatment with myricetin of 100, 200 and 400 mg/kg(59. 10±9. 97)%, (62. 10±6. 07)% and(77. 10±8. 87)%, of which the 400 mg/kg group was statistically significant(P<0. 05); the ratio of Bax/Bcl-2 in the model group was 5. 92±1. 45, and the ratio of Bax/Bcl-2 decreased after treatment with myricetin of 100, 200 and 400 mg/kg, which were 2. 52±0. 51, 1. 71±0. 52 and 1. 07±0. 29. There were statistical differences(P<0. 05 or P<0. 01). CONCLUSION: Myrica flavone can protect sperm mitochondrial membrane potential, inhibit testicular cell apoptosis, and protect the male mice from reproductive toxicity induced by cyclophosphamide.


Assuntos
Flavonoides , Motilidade Espermática , Animais , Ciclofosfamida/toxicidade , Flavonoides/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
2.
Wei Sheng Yan Jiu ; 49(5): 795-801, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070827

RESUMO

OBJECTIVE: To study effect of nano-selenium and nano-cerium(nano cerium oxide) on the spermatogenic ability of mice irradiated by 1800 MHz microwave radiation(MR). METHODS: Forty-two ICR mice were randomly divided into groups: blank control group, solvent control group, microwave radiation model group, low, medium and high dose groups of nano-selenium+nano-cerium. In joint effects groups of nano-selenium and nano-cerium, the nano-selenium solution(60, 120 and 240 µg/kg) and the nano-cerium oxide solution(15, 30, 60 µg/kg) were administered to the stomach at 7:30 in the morning and 18:30 in the evening, respectively. The blank control group was orally administered with an equal volume of distilled water, and the solvent control group and the MR group were orally administered with an equal volume of carboxymethylcellulose sodium solution. During the second week of gastric administration, the mice were exposed to microwave radiation(1800 MHz) for 2 h every day(specific absorption ratio: 0. 2986 W/kg). After MR treatment, the daily sperm production of testis, sperm motility and sperm deformity rate in epididymis were measured, and the testicular marker enzymes [G6 PDH(6-phosphatedehydrogenase), ACP(acid phosphatase), LDH(lactate dehydrogenase)], antioxidant indexes [CAT(catalase), MDA(malondialdehyde) and T-AOC(total antioxidant capacity)] in testicular tissue were analyzed. RESULTS: Compared with the solvent control group, MR led to the decrease of sperm motility and the increase of sperm deformity rate, decreased the enzymes activities of G6 PDH, ACP and CAT, increased LDH activity and MDA content, and decreased the T-AOC level in testicular tissue, and the differences were statistically significant(P<0. 05). Compared with the MR group, the joint action of nano-selenium and nano-cerium with medium dose increased the daily sperm production of testis((18. 98±1. 27) ×10~6/g) vs. (15. 53±1. 24) ×10~6/g), decreased the sperm deformity rate(11. 74%±0. 91% vs. 16. 84%±2. 05%), and the joint action of nano-selenium and nano-cerium with medium and high dose increased the sperm motility in epididymis(61. 98%±6. 33%, 54. 17±4. 38 vs. 45. 16%±5. 01%), and the differences were statistically significant(P<0. 05). Compared with the MR group, the joint action of nano-selenium and nano-cerium with low and medium dose increased the activity of ACP(11. 07±0. 98, 14. 85±1. 39 vs. 8. 72±0. 91 nmol/(min·mg prot), P<0. 05). The joint action of nano-selenium and nano-cerium with medium and high dose increased the activity of G6 PDH(24. 12±2. 06, 21. 36±3. 65 vs. 15. 11±1. 73 nmol/(min·mg prot), P<0. 05) and decreased the activity of LDH(15. 52±1. 17, 13. 51±1. 68 vs. 22. 46±2. 01 nmol/(min·mg prot), P<0. 05). The joint action of nano-selenium and nano-cerium with medium dose increased the activity of CAT(17. 92±2. 03 vs. 11. 69±0. 87 nmol/(min·mg prot), P<0. 05) and decreased the content of MDA(5. 17 ±0. 62 vs. 9. 03 ±0. 63 nmol/mg prot, P<0. 05). The joint action of nano-selenium and nano-cerium with low, medium and high dose increased the level of T-AOC(22. 06±1. 54, 29. 36±2. 39, 21. 01±2. 47 vs. 12. 88±1. 82 U/mg prot, P<0. 05). CONCLUSION: The joint addition of nano-selenium and nano-cerium can improve the reproductive function of male mice exposed to MR, and can effectively alleviate the changes of mouse testicular marker enzyme activity and the decline of antioxidant capacity caused by MR.


Assuntos
Selênio , Animais , Antioxidantes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Micro-Ondas , Motilidade Espermática
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(4): 463-468, 2020 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895131

RESUMO

OBJECTIVE: To investigate the protective effects of dexmedetomidine (DEX) against cerebral ischemia/reperfusion (I/R) injury in mice and its relation with mitochondrial fusion and fission. METHODS: Male ICR mice were randomly divided into sham-operated group, I/R group, I/R+DEX group and I/R+DEX+dorsomorphin group. Mouse models of cerebral I/R injury were established by modified thread occlusion of the middle cerebral artery. DEX (50 µg/kg) was injected intraperitoneally at 30 min before cerebral ischemia, which lasted for 1 h followed by reperfusion for 24 h. The neurobehavioral deficits of the mice were evaluated based on Longa's scores. The volume of cerebral infarction was detected by TTC staining. The changes in mitochondrial morphology of the brain cells were observed with transmission electron microscopy. Western blotting was performed to detect the expressions of phosphorylated AMP-activated protein kinase (p-AMPK), mitochondrial fusion protein (Mfn2) and mitochondrial fission protein (p-Drp1) in the brain tissues. RESULTS: DEX pretreatment significantly reduced the neurobehavioral score and the percent volume of cerebral infarction in mice with cerebral I/R injury. Treatment with dorsomorphin (an AMPK inhibitor) in addition to DEX significantly increased the neurobehavioral score and the percent volume of cerebral infarction in the mouse models. Transmission electron microscopy showed that DEX obviously reduced mitochondrial damage caused by cerebral I/R injury and restored mitochondrial morphology of the brain cells, and such effects were abolished by dorsomorphin treatment. Western blotting showed that DEX pretreatment significantly increased the expressions of p-AMPK and Mfn2 protein and decreased the expression of p-Drp1 protein in the brain tissue of the mice, and these changes were also reversed by dorsomorphin treatment. CONCLUSIONS: Preconditioning with DEX produces protective effects against cerebral I/R injury in mice possibly by activating AMPK signaling to regulate mitochondrial fusion and fission in the brain cells.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Dexmedetomidina , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dinâmica Mitocondrial
4.
Acta Cir Bras ; 35(8): e202000802, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32901679

RESUMO

PURPOSE: To investigate the effects of grape seed proanthocyanidin B2 (GSPB2) preconditioning on oxidative stress and apoptosis of renal tubular epithelial cells in mice after renal ischemia-reperfusion (RIR). METHODS: Forty male ICR mice were randomly divided into 4 groups: Group A: mice were treated with right nephrectomy. Group B: right kidney was resected and the left renal vessel was clamped for 45 minutes. Group C: mice were intraperitoneally injected with GSPB2 before RIR established. Group D: mice were intraperitoneally injected with GSPB2 plus brusatol before RIR established. Creatinine and urea nitrogen of mice were determined. Pathological and morphological changes of kidney were checked. Expressions of Nrf-2, HO-1, cleaved-caspase3 were detected by Western-blot. RESULTS: Compared to Group B, morphology and pathological damages of renal tissue were less serious in Group C. Western-blot showed that expressions of Nrf-2 and HO-1 in Group C were obviously higher than those in Group B. The expression of cleaved-caspase3 in Group C was significantly lower than that in Group B. CONCLUSION: GSPB2 preconditioning could attenuate renal oxidative stress injury and renal tubular epithelial cell apoptosis by up-regulating expressions of Nrf-2 and HO-1 and down-regulating the expression of cleaved-caspase-3, but the protective effect could be reversed by brusatol.


Assuntos
Apoptose , Extrato de Sementes de Uva , Estresse Oxidativo , Proantocianidinas , Traumatismo por Reperfusão , Animais , Apoptose/efeitos dos fármacos , Células Epiteliais , Extrato de Sementes de Uva/farmacologia , Extrato de Sementes de Uva/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Proantocianidinas/farmacologia , Proantocianidinas/uso terapêutico
5.
Nat Commun ; 11(1): 4576, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917905

RESUMO

Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs). The mechanism underlying lipid supply for this process and its pathophysiological relevance remains unclear, however. Here, we identify PDZD8-the mammalian ortholog of a yeast ERMES subunit-as a protein that interacts with protrudin, which is located at ER-LyLE MCSs. Protrudin and PDZD8 promote the formation of ER-LyLE MCSs, and PDZD8 shows the ability to extract various lipids from the ER. Overexpression of both protrudin and PDZD8 in HeLa cells, as well as their depletion in mouse primary neurons, impairs endosomal homeostasis by inducing the formation of abnormal large vacuoles reminiscent of those apparent in spastin- or REEP1-deficient neurons. The protrudin-PDZD8 system is also essential for the establishment of neuronal polarity. Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Endossomos/fisiologia , Metabolismo dos Lipídeos , Neurônios/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Feminino , Células HEK293 , Células HeLa , Humanos , Lipídeos , Lipossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Mitocôndrias , Domínios Proteicos , Proteômica , Proteínas Recombinantes , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/genética
6.
Zhongguo Zhong Yao Za Zhi ; 45(16): 3812-3818, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893575

RESUMO

The current study was conducted to explore the effects of light intensity in cultivating environment on the cleaning away heat property of Viola yedoensis. In the present study, we established the acute inflammation model of ICR mice by injecting carrageenan. We compared the effects of V. yedoensis grown under different light intensities(100%, 80%, 50%, 35% and 5% of full sunlight) on mice body temperature, thermal radiation and the swelling degree of foot tissue before and after modeling observing by thermal infrared imaging technique and weighing method. The changes of energy metabolism related enzymes in liver were detected by enzyme-linked immunosorbent assay(ELISA). In addition, the effects of V. yedoensis grown under different light intensities on human lung cancer cell A549 proliferation were explored with MTT method. The results showed that the body temperature of all groups of mice in V. yedoensis group were significantly lower than that of the blank group, except 5% full sunlight group, and the body temperature declined in positive proportion to light intensity. V. yedoensis group could alleviate foot swelling, reduce SDH activity in liver tissue(especially 100% full sunlight group and 80% full sunlight group were significantly lower than model group), and the degree of alleviating and reducing was positively correlated with light intensity. There was no significant difference in the activity of Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase in liver tissue among treatments. The contents of IL-1ß, IL-6, TNF-α, PGE_2 in foot tissue of mice in V. yedoensis groups were significantly lower than those in model group. Among them, the lowest levels of IL-1ß, IL-6, TNF-α, PGE_2 were found in 80% full sunlight group, and there was no significant difference in TNF-α among different groups. The effects of V. yedoensis aqueous extract on A549 cell line proliferation inhibition rate increased with the light intensities of V. yedoensis cultivating environment. And the effects of V. yedoensis grown under 100% of full sunlight showed significantly higher A549 cell line proliferation inhibition rate compared with other groups(P<0.05). In summary, the light intensity of V. yedoensis cultivating environment is positively correlated with the cleaning away heat property of V. yedoensis, which conforms to the "light-cold and heat property" hypothesis,The V. yedoensis should be planted under full light according.


Assuntos
Viola , Animais , Temperatura Alta , Inflamação , Camundongos , Camundongos Endogâmicos ICR , Fator de Necrose Tumoral alfa
7.
Korean J Parasitol ; 58(4): 461-466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32871641

RESUMO

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.


Assuntos
Isquemia Encefálica/prevenção & controle , Encéfalo/parasitologia , Interações Hospedeiro-Parasita , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroproteção , Toxoplasma/fisiologia , Toxoplasmose/fisiopatologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/parasitologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos ICR , Tamanho do Órgão , Toxoplasmose/metabolismo , Toxoplasmose/patologia
8.
Am J Chin Med ; 48(6): 1385-1407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907359

RESUMO

Accumulating evidence suggests that gut microbiota plays a crucial role in the development of metabolic diseases, especially type 2 diabetes mellitus (T2DM). The nutrient-rich resource Cornus Fructus (CF) showed curative effects on diabetes mellitus. However, the mechanism underlying its hyperglycemic activity remains obscure. Herein, the antidiabetic potential of four extracts from CF, including saponin (CTS), iridoid glycoside (CIG), tannin (CT), and alcohol extract (CCA) was evaluated in vivo. The results showed that all four extracts could increase the body weight, decrease the blood glucose levels, and elevate the glucose tolerance. Moreover, insulin sensitivity and lipid profile were significantly improved in fed mice. In the [Formula: see text]-diversity index of samples, compared to the DM group, the diversity and richness of gut microbiota in mice to a certain extent were reduced in both CF extracts and Metformin (PC). Among them, there was statistical significance in PC (ACE, [Formula: see text]) and CCA (ACE, [Formula: see text]; chao1: [Formula: see text]). Beta diversity showed the same trend as the UPGMA clustering trees, which revealed that CF extracts could improve intestinal homeostasis in T2DM mice. Also, CF extracts could elevate the production of short-chain fatty acids, as well as regulate the composition of gut microbiota. The key bacteria related to T2DM including Firmicutes, Bacteroides, Lactobacillus, and Clostridium were modulated by metformin and CF. Altogether, CF is a potential nutrient-rich candidate that can be used in functional foods for the treatment of T2DM, and the change of gut microbiota might be a novel mechanism underlying its hyperglycemic activity.


Assuntos
Cornus/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Alimento Funcional , Resistência à Insulina , Glicosídeos Iridoides , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Saponinas , Taninos
9.
Environ Pollut ; 266(Pt 3): 115276, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32835916

RESUMO

Tributyltin (TBT), an organotin compound once widely used in agriculture and industry, has been reported to induce obesity and endocrine disruption. Gut microbiota has a strong connection with the host's physiology. Nevertheless, the influences of TBT exposure on gut microbiota and whether TBT-influenced gut microbiota is related to TBT-induced toxicity remain unclear. To fill these gaps, ICR (CD-1) mice were respectively exposed to TBT at NOEL (L-TBT) and tenfold NOEL (H-TBT) daily by gavage for 8 weeks in the current study. The results showed that TBT exposure significantly increased body weight as well as epididymal fat, and led to adipocyte hypertrophy, dyslipidemia and impaired glucose and insulin homeostasis in mice. Additionally, TBT exposure significantly decreased the levels of T4, T3 and testosterone in serum. Also of note, TBT exposure changed gut microbiota composition mainly by decreasing Bacteroidetes and increasing Firmicutes proportions. To confirm the role of gut microbiota in TBT-induced overweight and hormonal disorders, fecal microbiota transplantation was performed and the mice receiving gut microbiota from H-TBT mice had similar phenotypes with their donor mice including significant body weight and epididymal fat gain, glucose and insulin dysbiosis and hormonal disorders. These results suggested that gut microbiome altered by TBT exposure was involved in the TBT-induced increased body weight, impaired glucose and insulin homeostasis and endocrine disruption in mice, providing significant evidence and a novel perspective for better understanding the mechanism by which TBT induces toxicity.


Assuntos
Microbioma Gastrointestinal , Animais , Peso Corporal , Glucose , Homeostase , Insulina , Camundongos , Camundongos Endogâmicos ICR , Compostos de Trialquitina
10.
Chem Biol Interact ; 329: 109217, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32750324

RESUMO

Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration.


Assuntos
Encéfalo/metabolismo , Cobalto/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Reguladoras do Ferro/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cobalto/metabolismo , Feminino , Hepcidinas/genética , Hepcidinas/metabolismo , Ferro/metabolismo , Proteínas Reguladoras do Ferro/genética , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
11.
Toxicol Appl Pharmacol ; 404: 115182, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763356

RESUMO

Due to the pandemic of coronavirus disease 2019, the use of disinfectants is rapidly increasing worldwide. Didecyldimethylammonium chloride (DDAC) is an EPA-registered disinfectant, it was also a component in humidifier disinfectants that had caused idiopathic pulmonary diseases in Korea. In this study, we identified the possible pulmonary toxic response and mechanism using human bronchial epithelial (BEAS-2B) cells and mice. First, cell viability decreased sharply at a 4 µg/mL of concentration. The volume of intracellular organelles and the ROS level reduced, leading to the formation of apoptotic bodies and an increase of the LDH release. Secretion of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and matrix metalloproteinase-1 also significantly increased. More importantly, lamellar body-like structures were formed in both the cells and mice exposed to DDAC, and the expression of both the indicator proteins for lamellar body (ABCA3 and Rab11a) and surfactant proteins (A, B, and D) was clearly enhanced. In addition, chronic fibrotic pulmonary lesions were notably observed in mice instilled twice (weekly) with DDAC (500 µg), ultimately resulting in death. Taken together, we suggest that disruption of pulmonary surfactant homeostasis may contribute to DDAC-induced cell death and subsequent pathophysiology and that the formation of lamellar body-like structures may play a role as the trigger. In addition, we propose that the cause of sudden death of mice exposed to DDAC should be clearly elucidated for the safe application of DDAC.


Assuntos
Betacoronavirus/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Compostos de Amônio Quaternário/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Compostos de Amônio Quaternário/administração & dosagem
12.
Nat Commun ; 11(1): 4076, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796851

RESUMO

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3-/-Rag1-/- and circKcnt2-/-Rag1-/- mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.


Assuntos
Colite/imunologia , Colite/metabolismo , Linfócitos/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo , RNA Circular/metabolismo , Animais , Colite/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/genética , Homeostase , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/patologia , Intestinos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Canais de Potássio Ativados por Sódio/genética , RNA Circular/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Fatores de Transcrição/genética
13.
Int J Nanomedicine ; 15: 5073-5082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764937

RESUMO

Objective: To prepare xanthatin (XA)-loaded polydopamine (PDA) nanoparticles (PDA-XA-NPs) and to investigate their adhesion and bioavailability. Materials and methods: PDA-XA-NPs were synthesized and characterized using transmission electron microscopy, zeta potential analysis and encapsulation efficiency analysis. Their in vitro release kinetics and inhibitory effects on gastric cancer were studied. The adhesion of PDA-XA-NPs was evaluated by in vivo imaging atlas. The pharmacokinetics of PDA-XA-NPs and XA was compared. Results: PDA-XA-NPs had a spherical shape, a particle size of about 380 nm, an encapsulation efficiency of (82.1 ± 0.02) % and a drug loading capacity of (5.5 ± 0.1)%. The release of PDA-XA-NPs in PBS was stable and slow, without being affected by pH. The adhesion capacity of PDA-XA-NPs for mucin was significantly higher than that of bulk drug. The gastric mucosal retention of PDA-XA-NPs reached 89.1% which significantly exceeded that of XA. In vivo imaging showed that PDA-XA-NPs targeting the stomach were retained for a period of time. The pharmacokinetics study showed that PDA-XA-NPs had a longer retention time and a slower drug release than those of XA. In vitro experiments confirmed that PDA-XA-NPs exerted similar inhibitory effects on gastric cancer to those of XA, which lasted for a period of time. Conclusion: High-adhesion NPs were constructed. Gastric cancer was targeted by orally administered PDA-XA-NPs, as a potentially feasible therapy. Eventually, the bioavailability of XA was increased.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Furanos/farmacocinética , Nanopartículas/química , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Furanos/química , Mucosa Gástrica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Masculino , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Nanopartículas/metabolismo , Tamanho da Partícula , Polímeros/química , Ratos Sprague-Dawley , Neoplasias Gástricas/patologia
14.
Int J Nanomedicine ; 15: 5459-5471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801700

RESUMO

Purpose: Indocyanine green (ICG), a near infrared (NIR) dye clinically approved in medical diagnostics, possesses great heat conversion efficiency, which renders itself as an effective photosensitizer for photothermal therapy (PTT) of cancer. However, there remain bottleneck challenges for use in PTT, which are the poor photo and plasma stability of ICG. To address these problems, in this research, ICG-loaded silver nanoparticles were prepared and evaluated for the applicability as an effective agent for photothermal cancer therapy. Methods and Results: PEGylated bovine serum albumin (BSA)-coated silver core/shell nanoparticles were synthesized with a high loading of ICG ("PEG-BSA-AgNP/ICG"). Physical characterization was carried out using size analyzer, transmission electron microscopy, and Fourier transform infrared spectrophotometry to identify successful preparation and size stability. ICG-loading content and the photothermal conversion efficiency of the particles were confirmed with inductively coupled plasma mass spectrometry and laser instruments. In vitro studies showed that the PEG-BSA-AgNP/ICG could provide great photostability for ICG, and their applicability for PTT was verified from the cellular study results. Furthermore, when the PEG-BSA-AgNP/ICG were tested in vivo, study results exhibited that ICG could stably remain in the blood circulation for a markedly long period (plasma half-life: 112 min), and about 1.7% ID/g tissue could be accumulated in the tumor tissue at 4 h post-injection. Such nanoparticle accumulation in the tumor enabled tumor surface temperature to be risen to 50°C (required for photo-ablation) by laser irradiation and led to successful inhibition of tumor growth in the B16F10 s.c. syngeneic nude mice model, with minimal systemic toxicity. Conclusion: Our findings demonstrated that PEG-BSA-AgNPs could serve as effective carriers for delivering ICG to the tumor tissue with great stability and safety.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas Metálicas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Difusão Dinâmica da Luz , Meia-Vida , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Melanoma Experimental/tratamento farmacológico , Camundongos Endogâmicos ICR , Camundongos Nus , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química , Soroalbumina Bovina/química , Prata/química , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Life Sci ; 258: 118214, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768585

RESUMO

Large numbers of rodents are often used in the study of disease progression and in the evaluation of its potential treatments. To avoid subjective observation and to minimize home cage interference, we developed a computerized home cage monitoring system (HCMS100) based on a standard cage rack adapted with a single laser beam and a detector mounted on each cage, enabling to monitor mice movements based on laser beam interruptions. This retrofit system provided continuous and uninterrupted monitoring of spontaneous movement of a group of mice in a home cage. Validity was evaluated using disease state induced by LPS modelling bacterial infection and by influenza virus. RESULTS: Spontaneous activity of different number of mice (2-8) per cage showed the expected circadian rhythm with increased activity during the night, and its extent dependent on the number of mice in the cage. Females and males show similar circadian rhythm. Intranasal LPS administration and pulmonary infection with live influenza virus resulted in major reduction of mice activity along disease progression. Increase in activity over time was a good indicator of the recovery process from both LPS exposure and the flu infection. CONCLUSIONS: HCMS100 was shown to be a reliable, inexpensive, easy to use system that requires no changes in the common housing of various experimental animals (mice, hamsters, rats etc.). With minimal intervention, HCMS100 provides a continuous record of group activity with clear pattern of circadian rhythm, allowing long term recording of home cage activity even in restricted access environments.


Assuntos
Progressão da Doença , Abrigo para Animais , Lipopolissacarídeos/toxicidade , Infecções por Orthomyxoviridae/fisiopatologia , Orthomyxoviridae , Recuperação de Função Fisiológica/fisiologia , Animais , Ritmo Circadiano/fisiologia , Feminino , Abrigo para Animais/tendências , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Infecções por Orthomyxoviridae/psicologia , Recuperação de Função Fisiológica/efeitos dos fármacos
16.
Life Sci ; 258: 118195, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781073

RESUMO

AIMS: The estrogen-ERα axis participates in osteoblast maturation. This study was designed to further evaluated the roles of the estrogen-ERα axis in bone healing and the possible mechanisms. MAIN METHODS: Female ICR mice were created a metaphyseal bone defect in the left femurs and administered with methylpiperidinopyrazole (MPP), an inhibitor of ERα. Bone healing was evaluated using micro-computed tomography. Colocalization of ERα with alkaline phosphatase (ALP) and ERα translocation to mitochondria were determined. Levels of ERα, ERß, PECAM-1, VEGF, and ß-actin were immunodetected. Expression of chromosomal Runx2, ALP, and osteocalcin mRNAs and mitochondrial cytochrome c oxidase (COX) I and COXII mRNAs were quantified. Angiogenesis was measured with immunohistochemistry. KEY FINDINGS: Following surgery, the bone mass was time-dependently augmented in the bone-defect area. Simultaneously, levels of ERα were specifically upregulated and positively correlated with bone healing. Administration of MPP to mice consistently decreased levels of ERα and bone healing. As to the mechanisms, osteogenesis was enhanced in bone healing, but MPP attenuated osteoblast maturation. In parallel, expressions of osteogenesis-related ALP, Runx2, and osteocalcin mRNAs were induced in the injured zone. Treatment with MPP led to significant inhibition of the alp, runx2, and osteocalcin gene expressions. Remarkably, administration of MPP lessened translocation of ERα to mitochondria and expressions of mitochondrial energy production-related coxI and coxII genes. Furthermore, exposure to MPP decreased levels of PECAM-1 and VEGF in the bone-defect area. SIGNIFICANCE: The present study showed the contributions of the estrogen-ERα axis to bone healing through stimulation of energy production, osteoblast maturation, and angiogenesis.


Assuntos
Regeneração Óssea , Diferenciação Celular , Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Neovascularização Fisiológica , Osteoblastos/citologia , Transdução de Sinais , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Diferenciação Celular/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
17.
Cell ; 182(5): 1271-1283.e16, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32795413

RESUMO

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.


Assuntos
RNA Mensageiro/genética , RNA Viral/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Chlorocebus aethiops , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Células HeLa , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Th1/imunologia , Potência de Vacina , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Células Vero , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
18.
J Pharmacol Sci ; 144(2): 76-82, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32736867

RESUMO

Astrocytes, comprising the primary glial-cell type, are involved in the formation and maturation of synapses, and thus contribute to sustainable synaptic transmission between neurons. Given that the animals in higher phylogenetic tree have brains with a higher density of glial cells with respect to neurons, there is a possibility that the relative astrocytic density directly influences synaptic transmission. However, the notion has not been tested thoroughly. Here we addressed it, by using a primary culture preparation where single hippocampal neurons are surrounded by a variable but a countable number of cortical astrocytes in dot-patterned microislands, and recording synaptic transmission by patch-clamp electrophysiology. Neurons with a higher astrocytic density showed a higher amplitude of the evoked excitatory postsynaptic current than that of neurons with a lower astrocytic density. The size of the readily releasable pool of synaptic vesicles per neuron was significantly larger. The frequency of spontaneous synaptic transmission was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was comparable, but the percentage of functional ones was increased, indicating a lower ratio of presynaptically silent synapses. Taken together, the higher astrocytic density enhanced excitatory synaptic transmission by increasing the fraction of functional synapses through presynaptic un-silencing.


Assuntos
Astrócitos/fisiologia , Encéfalo/citologia , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Astrócitos/patologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores , Feminino , Camundongos Endogâmicos ICR , Neurônios/patologia , Filogenia , Gravidez
19.
J Environ Sci Health B ; 55(9): 803-812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32602772

RESUMO

Organophosphorus pesticides induce gender-specific developmental neurotoxicity after birth, especially in adolescents and adults. However, whether and when the selectivity occurs in fetus remains unclear. In this study, we analyzed chlorpyrifos (CPF)-induced neurotoxicity in the early fetal brains of male and female mice. The gestational dams were administered 0, 1, 3, and 5 mg/(kg.d) CPF during gestational days (GD)7-11, and brains from the fetuses were isolated and analyzed on GD12. Fetal gender was identified by PCR technique based on male-specific Sry gene and Myog control gene. The body weight and head weight, the activity of acetylcholinesterase (AChE), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and the content of malondialdehyde (MDA), as well as the oxidative stress-related gene expression were examined. Our results showed that CPF pretreatment induced AChE inhibition in GD12 fetal brain. CPF treatment activated SOD and GPX but not CAT and MDA. For oxidative stress-related gene expression, CPF pretreatment increased mRNA expression of Sod1, Cat, Gpx1, and Gpx2 in the fetal brain on GD12. The statistical analysis did not show gender-selective CPF-induced toxicity. Moreover, our results showed that although the gestational exposure to CPF could elicit abnormalities in the early fetal brain, the toxicity observed was not gender-specific.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Clorpirifos/toxicidade , Inseticidas/toxicidade , Acetilcolinesterase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Inibidores da Colinesterase/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fatores Sexuais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Testes de Toxicidade/métodos
20.
Exp Parasitol ; 216: 107946, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32622941

RESUMO

This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection.


Assuntos
Citocinas/metabolismo , Malária/imunologia , Malária/patologia , Plasmodium berghei/imunologia , Receptor para Produtos Finais de Glicação Avançada/fisiologia , Animais , Encéfalo/parasitologia , Encéfalo/patologia , Citocinas/sangue , Rim/parasitologia , Rim/patologia , Modelos Lineares , Fígado/parasitologia , Fígado/patologia , Pulmão/parasitologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Parasitemia/imunologia , Distribuição Aleatória , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/imunologia , Baço/parasitologia , Baço/patologia
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