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1.
Biochem Biophys Res Commun ; 612: 154-161, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35526496

RESUMO

Recent studies showed that in responding of pathogens stimulation, immune cells and other cells display memory-like effects. Platelets are primary effectors of hemostasis and thrombosis which also participate in immune responses. However, there is no relevant research on whether memory-like effect exists in platelets. In our study after recovery from repetitive LPS stimulus, platelets aggregation, diffusion and clot retraction exhibit a significant reduction. It proves that memory-like response could be aroused in platelets. Furthermore, in the mouse arterial thrombosis model, LPS pretreated platelets showed lower integrin activation, shorter thrombus length and longer occlusion time, indicating that the memory-like response of platelet could alleviate arterial thrombosis. Moreover, memory-like response of platelets was also found to be related to PI3K/AKT signaling pathway. The decreased mitochondrial DNA methylation reveal that platelet memory-like responses may be produced from epigenetic reprogramming. Our research proves for the first time that memory-like response in platelets protects mice from arterial thrombosis, extends the understanding of trained memory.


Assuntos
Plaquetas , Trombose , Animais , Plaquetas/metabolismo , Modelos Animais de Doenças , Hemostasia , Lipopolissacarídeos/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Ativação Plaquetária , Agregação Plaquetária , Trombose/metabolismo
2.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202717

RESUMO

Timosaponin BII is one of the most abundant Anemarrhena saponins and is in a phase II clinical trial for the treatment of dementia. However, the pharmacological activity of timosaponin BII does not match its low bioavailability. In this study, we aimed to determine the effects of gut microbiota on timosaponin BII metabolism. We found that intestinal flora had a strong metabolic effect on timosaponin BII by HPLC-MS/MS. At the same time, seven potential metabolites (M1-M7) produced by rat intestinal flora were identified using HPLC/MS-Q-TOF. Among them, three structures identified are reported in gut microbiota for the first time. A comparison of rat liver homogenate and a rat liver microsome incubation system revealed that the metabolic behavior of timosaponin BII was unique to the gut microbiota system. Finally, a quantitative method for the three representative metabolites was established by HPLC-MS/MS, and the temporal relationship among the metabolites was initially clarified. In summary, it is suggested that the metabolic characteristics of gut microbiota may be an important indicator of the pharmacological activity of timosaponin BII, which can be applied to guide its application and clinical use in the future.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Saponinas/farmacocinética , Esteroides/farmacocinética , Animais , Biotransformação , Masculino , Ratos , Ratos Sprague-Dawley , Saponinas/farmacologia , Esteroides/farmacologia
3.
J Pharmacol Sci ; 144(1): 43-51, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653340

RESUMO

Platelet activation is the primary cause of thrombosis. The P2X7 receptor (P2X7R) is a therapeutic target of thrombosis. However, it is still unknown whether P2X7R activation affects platelet thrombus. Our molecular docking results showed that entecavir as a P2X7R antagonist interacted perfectly with the human P2X7R (hP2X7R) in silico simulation studies. Furthermore, our experimental data revealed that entecavir could act as a P2X7R antagonist to exert cytoprotective effects against platelet activation via protecting mitochondrial function, improving lipid peroxidation and increasing antioxidant activity. Correlated with this, entecavir inhibited platelet aggregation, dense-granule secretion, P-selectin expression, integrin activation and Ca2+ increase. In experimental mouse model, entecavir could significantly inhibit arteriovenous thrombosis and prolong the bleeding time. Furthermore, we found that entecavir had no significant effect on prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FIB), mean platelet volume (MPV) and platelet counts (PLT). This study demonstrates that entecavir markedly prevents platelet activation and thrombosis through inhibiting P2X7R without affecting coagulation system. Therefore, entecavir may be a potential candidate for treating thrombosis disease.


Assuntos
Guanina/análogos & derivados , Ativação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7 , Trombose/prevenção & controle , Animais , Antioxidantes , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Agregação Plaquetária/efeitos dos fármacos , Trombose/sangue
4.
Biol Pharm Bull ; 43(6): 985-993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32475920

RESUMO

Acute biliary pancreatitis (ABP) with a high mortality rate is an incurable digestive system disease induced by abnormal bile acid regurgitation due to the biliary obstruction. Dehydrocholic acid (DA) alleviates the severity of cholestatic hepatitis related to biliary inflammation, suggesting DA is potential to develop for the incurable ABP management. Here we identified DA potency and explored the underlying mechanism in ABP. Our data showed that DA administration not only reduced typically clinicopathological parameters including serum levels of amylase and lipase but also suppressed pancreatic tissue edema, necrosis and trypsin activation in ABP mice. We also found that DA significantly reduced the necrosis of pancreatic acinar cells induced by sodium taurocholate (NaT). Further experimental data showed the significant inhibitions of DA on mitochondrial membrane potential depolarization, ATP exhaustion, calcium overload and reactive oxygen species (ROS) erupted in acinar cells induced by NaT, indicating DA could avert acinar cell death through protecting the mitochondrial function, scavenging excessive oxidative stress and balancing calcium. The comprehensive study found DA elevated the expression of transcription factor EB (TFEB) in vitro thus to increase the functional lysosome content. Indeed, DA decreased the Microtubule-associated protein light chain 3 (LC3) II/I ratio as well as ubiquitin-binding protein p62 and Parkin expressions in vivo and in vitro, revealing autophagy restoration maybe through the improvement of TFEB-mediated lysosome biogenesis. These data indicate that DA improves ABP through the mitochondrial protection, antioxidant ability enhancement and autophagy recovery. In conclusion, our study proposes a potential therapy strategy for the incurable ABP.


Assuntos
Antioxidantes/uso terapêutico , Ácido Desidrocólico/uso terapêutico , Pancreatite/tratamento farmacológico , Células Acinares/efeitos dos fármacos , Amilases/sangue , Animais , Antioxidantes/farmacologia , Cálcio/metabolismo , Ácido Desidrocólico/farmacologia , Lipase/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ácido Taurocólico , Tripsina/metabolismo
5.
Cancer Cell Int ; 19: 170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297034

RESUMO

BACKGROUND: The Warburg effect demonstrates the importance of glycolysis in the development of primary and metastatic cancers. We aimed to explore the role of monocarboxylate transporter 1 (MCT1) and MCT4, two essential transporters of lactate, in renal cancer progression during cancer-endothelial cell co-culturing. METHODS: Renal cancer cells (786-O) and human vascular endothelial cells (HUVECs) were single-cultured or co-cultured in transwell membranes in the presence or absence of a MCT-1/MCT-4 specific blocker, 7ACC1. Cell proliferation was evaluated with the CCK-8 kit, while cell migration, after a scratch and invasion in transwell chambers, was evaluated under a microscope. Real-time qPCR and western blot were employed to determine the mRNA and protein levels of MCT1 and MCT4, respectively. The concentration of lactic acid in the culture medium was quantified with an l-Lactic Acid Assay Kit. RESULTS: 786-O cells and HUVECs in the co-culturing mode exhibited significantly enhanced proliferation and migration ability, compared with the cells in the single-culturing mode. The expression of MCT1 and MCT4 was increased in both 786-O cells and HUVECs in the co-culturing mode. Co-culturing promoted the invasive ability of 786-O cells, and markedly increased extracellular lactate. Treatments with 7ACC1 attenuated cell proliferation, migration, and invasion, and down-regulated the levels of MCT1/MCT4 expression and extracellular lactate. CONCLUSIONS: The Warburg effect accompanied with high MCT1/MCT4 expression in the cancer-endothelial microenvironments contributed significantly to renal cancer progression, which sheds new light on targeting MCT1/MCT4 and glycolytic metabolism in order to effectively treat patients with renal cancers.

6.
Bioorg Chem ; 83: 1-5, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30339860

RESUMO

Two new monoterpene indole alkaloids, naucleaoffines A (1) and B (2), together with six known alkaloids (3-8), were isolated from the stems and leaves of Nauclea officinalis. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with the data reported in literature. All isolated compounds were evaluated for their anti-inflammatory activities and anti-HIV-1 activities. Compounds 1-8 exhibited significant inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with IC50 values comparable to that of hydrocortisone. In addition, compounds 1-8 showed significant anti-HIV-1 activities with EC50 ranged from 0.06 to 2.08 µM. These findings suggest that the discoveries of these indole alkaloids with significant anti-inflammatory activities and anti-HIV-1 activities isolated from N. officinalis could be of great importance to the development of new anti-inflammatory and anti-HIV agents.


Assuntos
Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Alcaloides Indólicos/farmacologia , Monoterpenos/farmacologia , Rubiaceae/química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , HIV-1/efeitos dos fármacos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
7.
Sheng Li Xue Bao ; 71(5): 732-740, 2019 Oct 25.
Artigo em Zh | MEDLINE | ID: mdl-31646327

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.


Assuntos
Inflamação/patologia , Doença de Parkinson/patologia , Substância Negra/patologia , Animais , Barreira Hematoencefálica , Neurônios Dopaminérgicos/patologia , Humanos , Microglia , alfa-Sinucleína
8.
Zhonghua Nan Ke Xue ; 25(8): 749-753, 2019 Aug.
Artigo em Zh | MEDLINE | ID: mdl-32227721

RESUMO

HPV is a very common virus worldwide spread by direct contact and involved in male reproductive health-related diseases such as infertility, condyloma acuminatum, and penile cancer. The development of HPV vaccines has contributed to the effective prevention of various subtypes of HPV and protection of males from HPV infection, especially the partners of HPV-positive females, the men who have sex with men, and those with a psychological fear of HPV infection. Therefore, HPV vaccines play an important role in the protection of males.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Saúde Reprodutiva , Condiloma Acuminado/etiologia , Homossexualidade Masculina , Humanos , Masculino , Infecções por Papillomavirus/complicações , Neoplasias Penianas/etiologia , Minorias Sexuais e de Gênero
9.
Eur Radiol ; 28(6): 2612-2619, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29313119

RESUMO

PURPOSE: The aim of this study was to compare the distribution patterns of microcalcifications in thyroid cancers with benign cases. METHODS: In total, 358 patients having microcalcifications on ultrasonography were analysed. Microcalcifications were categorised according to the distribution patterns: (I) microcalcifications inside one (a) or more (b) suspected nodules, (II) microcalcifications not only inside but also surrounding a suspected single (a) or multiple (b) nodules, and (III) focal (a) or diffuse (b) microcalcifications in the absence of any suspected nodule. Differences in distribution patterns of microcalcifications in benign and malignant thyroid lesions were compared. RESULTS: We found that the distribution patterns of microcalcifications differed between malignant (n = 325) and benign lesions (n = 117) (X 2 = 9.926, p < 0.01). Benign lesions were classified as type Ia (66.7%), type Ib (29.1%) or type IIIa (4.3%). The specificity of type II and type IIIb in diagnosing malignant cases was 100%. Among malignant lesions, 172 locations were classified as type Ia, 106 as type Ib, 12 as type IIa, 7 as IIb, 7 as type IIIa and 19 as type IIIb. Accompanying Hashimoto thyroiditis was most frequent in type III (51.6%). CONCLUSIONS: Types II and IIIb are highly specific for cancer detection. Microcalcifications outside a nodule and those detected in the absence of any nodule should therefore be reviewed carefully in clinical practice. KEY POINTS: • A method to classify distribution patterns of thyroid microcalcifications is presented. • Distribution features of microcalcifications are useful for diagnosing thyroid cancers. • Microcalcifications outside a suspicious nodule are highly specific for thyroid cancers. • Microcalcifications without suspicious nodules should also alert the physician to thyroid cancers.


Assuntos
Calcinose/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Análise de Variância , Biópsia por Agulha Fina/métodos , Calcinose/classificação , Calcinose/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Médicos , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/classificação , Nódulo da Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Adulto Jovem
10.
BMC Pregnancy Childbirth ; 18(1): 275, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970030

RESUMO

BACKGROUND: To investigate the effect of different delivery modes and related obstetric factors on the short-term strength of the pelvic floor muscle after delivery in Chinese primipara. METHODS: A total of 4769 healthy Chinese primiparas at postpartum 6-8 weeks were interviewed. According to the difference of delivery mode, the selected primiparas were divided into 2 groups, including cesarean delivery group containing 2020 and vaginal delivery group containing 2749. All the vaginal deliveries were further divided into 3 groups, including episiotomy group containing 2279, perineal laceration group containing 398, and forceps assisted group containing72. The scales of their pelvic floor muscle (PFM) strengths were examined by specially trained personnel using digital palpation (Modified Oxford scale:0-5 grade). According to participants' willingness, if the PFM strength was weak (0 or 1 grade), at-home PFM training would be recommended and an electrical stimulation combined with biofeedback therapy would be conducted for them in hospital. Twelve weeks after delivery, the PFM strength would be measured again. For statistical analysis, t-test, one-way variance analysis, Chi-square analysis, Kruskal-Wallis test H, Mann-Whitney U test and Wilcoxon test were carried out. RESULTS: The PFM strength in cesarean delivery group was higher than in vaginal delivery group (p < 0.05). Among 3 vaginal delivery groups, the PFM strength in perineal laceration group was the highest (p < 0.05); however, there was no difference in PFM strength between episiotomy group and forceps assisted group (p>0.05). After accepting PFM training at home and therapy in hospital, 305 women showed increased PFM strength (p < 0.05). CONCLUSIONS: Vaginal delivery is an independent risk factor causing the damage of PFM, and episiotomy may cause injury of PFM. Through PFM training at home and therapy in hospital, those damage will resume as soon as possible in the short-time period after delivery.


Assuntos
Parto Obstétrico/efeitos adversos , Força Muscular/fisiologia , Distúrbios do Assoalho Pélvico/etiologia , Diafragma da Pelve/fisiopatologia , Adulto , Povo Asiático , Biorretroalimentação Psicológica/métodos , Parto Obstétrico/métodos , Terapia por Estimulação Elétrica/métodos , Feminino , Humanos , Paridade , Distúrbios do Assoalho Pélvico/epidemiologia , Distúrbios do Assoalho Pélvico/reabilitação , Período Pós-Parto/fisiologia , Gravidez , Fatores de Risco , Adulto Jovem
11.
Nanomedicine ; 14(3): 673-684, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29309910

RESUMO

Thrombosis is the leading cause of death in patients with cardiovascular disease in the world. Current antithrombotic agent aspirin has serious side effects such as higher bleeding risk and serious gastrointestinal ulcers. Diosgenin reported in clinical research could prevent thrombosis without side effects. However, poor bioavailability and low knowledge on its molecular targets limit its clinical application. A novel prodrug with antithrombotic effect was prepared based on conjugating diosgenin derivatives to PEG with Schiff-base bond. The prodrug with long blood circulation time and satisfying safety could self-assemble into micelles in water. The prodrug micelles with pH-responsibility could targetedly release diosgenin in position of thrombus in vivo. The results indicate that the prodrug micelles without bleeding risk and histological damages prevent thrombosis by inhibiting platelet activation and apoptosis. Our studies demonstrate that the prodrug micelles could obviously enhance the efficacy in the prevention of arterial thrombus and venous thrombus than aspirin.


Assuntos
Diosgenina/farmacologia , Sistemas de Liberação de Medicamentos , Hemorragia/prevenção & controle , Nanopartículas/administração & dosagem , Pró-Fármacos/farmacologia , Trombose/prevenção & controle , Animais , Diosgenina/administração & dosagem , Diosgenina/química , Fibrinolíticos/administração & dosagem , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Hemorragia/epidemiologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Nanopartículas/química , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Fatores de Risco
12.
World J Surg Oncol ; 16(1): 179, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185198

RESUMO

BACKGROUND: To validate the clinical value of simple rules in distinguishing malignant adnexal masses from benign ones and to explore the effect of simple rules for experienced and less-experienced sonographers. METHODS: Patients with persistent adnexal masses were enrolled between November 2013 and December 2015. All masses were proven through histological examinations. Five sets of diagnoses were made and compared with one another. Diagnosis 1 was made, according to the simple rules, by a trainee with little clinical diagnostic experience. Diagnoses 2 and 3 were made by experienced and less-experienced sonographers, respectively, according to their clinical experiences. With diagnosis 1 as a reference, the two sonographers were asked to provide a second diagnosis, which were diagnoses 4 and 5. The efficiency of the five sets of diagnoses was compared using ROC curves. RESULTS: In total, 75 malignant (37.7%) and 124 benign lesions (62.3%) were enrolled in this study. The mean diameter of the benign masses was obviously smaller than that of the malignant ones (6.8 ± 3.4 cm vs. 9.3 ± 4.9 cm, p < 0.01). The malignant ratio in postmenopausal women was much higher (66.1%) than that in the premenopausal population (25.7%) (p < 0.0001). Totally, 156 of the 199 cases (79.4%) resulted in conclusive diagnoses. Sensitivity and specificity were 98.4% and 73.9%, respectively, among the conclusive cases. The area under the ROC curve (Az) for the simple rule diagnosis was significantly lower than that for the experienced sonographer diagnosis (0.85 vs. 0.96, p < 0.0001); compared with the less-experienced sonographer, this difference was not significant (0.85 vs. 0.86, p = 0.9776). No significant difference was found in the comparison between the diagnoses made by the experienced sonographer before and after referencing the simple rule diagnosis (Az, 0.96 vs. 0.97, p = 0.2055). Using diagnosis 1 as a reference, the diagnostic performance of the less-experienced sonographer increased (from 0.86 to 0.92, p = 0.012); however, it was still lower than that of the experienced sonographer (Az, 96% vs. 92%, p = 0.0241). CONCLUSIONS: The simple rules was an appealing method for discriminating malignant masses from benign ones, particularly for a less-experienced sonographer.


Assuntos
Doenças dos Anexos/diagnóstico por imagem , Competência Clínica/normas , Pessoal de Saúde/normas , Ultrassonografia/normas , Doenças dos Anexos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
13.
Zhongguo Zhong Yao Za Zhi ; 43(24): 4878-4883, 2018 Dec.
Artigo em Zh | MEDLINE | ID: mdl-30717534

RESUMO

The chemical consituents from the stems and leaves of Psychotria serpens were separated and purified by column chromatographies with silica gel, ODS, Sephadex LH-20 and PR-HPLC. The structures of the isolated compounds were identified on the basis of physicochemical properties and spectroscopic analyses, as well as comparisons with the data reported in literature. 18 compounds were isolated from the 90% ethanol extract of the stems and leaves of P. serpens, which were identified as chrysin(1), acacetin(2), genkwanin(3), chrysoeriol(4), rhamnocitrin(5), isorhamnetin(6), tricin(7), jaceosidin(8), dillenetin(9), kumatakenin(10), ayanin(11), isosakuranetin(12), eriodictyol(13), homoeriodictyol(14), taxifolin(15), pomonic acid(16), fupenzic acid(17) and euscaphic acid(18). All compounds were isolated from the genus Psychotria for the first time.


Assuntos
Medicamentos de Ervas Chinesas , Psychotria , Folhas de Planta , Caules de Planta
14.
J Asian Nat Prod Res ; 19(3): 272-298, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27380052

RESUMO

A series of diosgenyl analogs were prepared from diosgenin to evaluate their anticancer activity and antithrombotic property. Analog 4, which had a spiroketal structure with a 6-aminohexanoic acid residue, exhibited the highest potency against all five tumor cell lines. It significantly blocked tumor growth, induced cell apoptosis and autophagy, and regulated cellular calcium concentration, mitochondrial membrane potential, adenosine triphosphate, and cell cycle. In addition, fluorescence-tagged compounds indicated that the analogs could rapidly accumulate in the cytoplasm, but no specific localization in the nucleus of cancer cells was observed. Furthermore, preliminary structure-activity relationship studies demonstrated that spiroketal analogs exhibit better antithrombotic activity than furostanic analogs, which exhibit the opposite effect by promoting thrombosis. Our study indicates that compound 4 may be a promising anticancer drug candidate for cancer patients with thromboembolism.


Assuntos
Diosgenina/análogos & derivados , Apoptose/efeitos dos fármacos , Cálcio/análise , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Tromboembolia/tratamento farmacológico
15.
Sheng Li Xue Bao ; 69(2): 146-158, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28435973

RESUMO

Acute fetal hypoxia (AFH) can elicit postnatal motor deficits and cognitive impairments. To test whether lifelong acclimatization to middle altitude (MA) hypoxia has protective effects on the impairments caused by AFH, ICR mice bred at 1 900 m altitude for 6-7 generations were evaluated under AFH. On gestation day 9 (GD 9), 13 (GD 13) or 17 (GD 17), pregnant mice received a single exposure to acute hypoxia (7% O2, 6 h). Physiological and neurodevelopmental behaviors, motor function (open field), spatial learning and memory (Morris water maze), and anxiety level (elevated plus maze) were examined in the offspring from neonate to adulthood. In the neonatal age, among all the physiological and behavioral landmarks, almost no differences were found in the hypoxia groups. In the juvenile period, no obvious impairments of motor function and anxiety level were found in the hypoxia groups. In the adult period, no obvious impairment of motor function was found in hypoxia groups; Interestingly, AFH groups' offspring showed normal or enhanced long-term spatial memory ability after AFH. These data suggest that AFH cause little abnormalities in the offspring of MA-adapted mice. To further investigate the underlying mechanisms, the neuronal numbers in behavior-related brain areas (accumbens nucleus, basal amygdala and hippocampus) were counted, and the physiological parameters of the blood were measured. The morphological data showed that no obvious neuronal necrosis was found in all hypoxia groups. In addition, blood tests showed that red blood corpuscle count, hemoglobin concentration and hematocrit levels in mice raised at MA were markedly higher in both males and females, compared with controls raised at the sea level. These data suggest that lifelong acclimatization to MA hypoxia has protective effects against development delay, motor deficits and spatial learning and memory impairments induced by AFH, and the protective effects may be due to higher hemoglobin concentration and hematocrit levels in the blood. The findings may provide a better understanding of fetal hypoxia and potential intervention treatments.


Assuntos
Aclimatação , Altitude , Transtornos Cognitivos/prevenção & controle , Hipóxia Fetal/fisiopatologia , Hipóxia , Animais , Animais Recém-Nascidos , Encéfalo , Cognição , Transtornos Cognitivos/fisiopatologia , Disfunção Cognitiva , Feminino , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/fisiopatologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Aprendizagem Espacial
16.
Bioorg Med Chem Lett ; 26(14): 3364-3369, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27217000

RESUMO

Current therapy for blood vessel thrombosis has the risk of leading to gastrointestinal bleeding and thrombocytopenia. We previously reported that a new derivative of diosgenin, compound 5, had significant anti-inflammatory activity superior to that of aspirin, prolonged bleeding time, and inhibited platelet aggregation in vitro. In the present study, we investigated the in vivo efficacy and safety of compound 5 using the ferric chloride (FeCl3)-induced arterial and venous thrombosis models in rats as well as its toxicity in mice. Compared with the control rats, those treated with compound 5 showed significantly less adenosine diphosphate (ADP)-induced platelet aggregation and a prolonged activated partial thromboplastin time mediated by the specific regulation of factor VIII. Furthermore, compound 5 significantly reduced the average length and weight of thrombi in both arteries and veins. These findings were similar to those of aspirin at the same dose. The safety evaluation revealed a much lower risk of bleeding and lesser gastric mucosal damage with compound 5 than with the same dose of aspirin. An oral dose of up to 575.5mg/kg showed no toxicity in mice. In conclusion, consistent with our in vitro findings, compound 5 exhibited an in vivo antithrombotic activity that was comparable to aspirin mainly by reducing platelet aggregation and regulating factor VIII, but with fewer side effects.


Assuntos
Diosgenina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/tratamento farmacológico , Administração Oral , Animais , Diosgenina/administração & dosagem , Diosgenina/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/química , Ratos , Relação Estrutura-Atividade , Trombose/patologia
17.
Connect Tissue Res ; 56(2): 99-105, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25602512

RESUMO

OBJECTIVES: To observe the age-related changes of sulfated glycosaminoglycan (sGAG) content of hip joint cartilage of elderly people based on Equilibrium Partitioning of an Ionic Contrast Agent (EPIC) micro-CT. METHODS: Seventy human hip cartilage-bone samples were collected from hip-fracture patients (ages 51-96) and divided into five groups (10 years in an age group). They were first immersed in 20% concentration of the contrast agent Meglumine Diatrizoate (MD) for 6 h at 37 °C, and then scanned by micro-CT. Following scanning, samples were stained for sGAG with toluidine blue. The X-ray attenuation and sGAG optical density were calculated by image processing. The correlation between X-ray attenuation and sGAG optical density was then analyzed. RESULTS: The X-ray mean attenuation of the cartilage increased by 18.81% from the 50-80 age groups (p < 0.01), but decreased by 7.15% in the 90 age group compared to the 80 age group. The X-ray mean attenuation of the superficial layer and middle layer increased by 31.60 % and 44.68% from the 50-80 age groups, respectively (p < 0.01), but reduced by 4.67% and 6.05% separately in the 90 age group. However, the deep layer showed no significant change with aging. The sGAG optical density showed a linear correlation (r = -0.91, p < 0.01) with the X-ray attenuation. CONCLUSION: The sGAG content of hip joint cartilage varied with aging in elderly people. The changes in superficial layer and middle layer were more evident than deep layer.


Assuntos
Cartilagem Articular/patologia , Glicosaminoglicanos/metabolismo , Articulação do Quadril/patologia , Osteoartrite do Quadril/patologia , Microtomografia por Raio-X , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste , Humanos , Pessoa de Meia-Idade , Microtomografia por Raio-X/métodos
18.
Urol Int ; 95(1): 1-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25823547

RESUMO

Bladder cancer relapse and treatment failure in most patients have often been attributed to chemoresistance in tumor cells and metastasis. Emerging evidence indicates that tumor heterogeneity may play an equally important role and extends to virtually all measurable properties of cancer cells. Although the idea of tumor heterogeneity is not new, little attention has been paid to applying it to understand and control bladder cancer progression. With the development of biotechnology, such as Gene sequencing, recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be considered a new insight in the treatment of bladder cancers.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias da Bexiga Urinária/fisiopatologia , Neoplasias da Bexiga Urinária/terapia , Progressão da Doença , Evolução Molecular , Humanos , Mutação , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas/citologia , Microambiente Tumoral , Neoplasias da Bexiga Urinária/genética
19.
J Mater Sci Mater Med ; 25(7): 1709-19, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24659100

RESUMO

To prepare a bioactive bone substitute, which integrates biphasic calcium phosphate (BCP) and rhBMP-2/silk fibroin (SF) microsphere, and to evaluate its characteristics. Hydroxyapatite and ß-tricalcium phosphate were integrated with a ratio of 60­40%. RhBMP-2/SF (0.5 µg/1 mg) microsphere was prepared, and its rhBMP-2-release kinetics was assed. After joining pore-forming agent (Sodium chloride, NaCl), porous BCP/rhBMP-2/SF were manufactured, and its characteristics and bioactivity in vitro were evaluated. Mean diameter of rhBMP-2/SF microsphere was 398.7 ± 99.86 nm, with a loading rate of 4.53 ± 0.08%. RhBMP-2 was released in a dual-phase pattern, of which fast-release (nearly half of protein released) focused on the initial 3 days, and slow-release sustained more than 28 days. With the increase in concentration of NaCl, greater was porosity and pore size, but smaller mechanical strength of BCP/rhBMP-2/SF. Material with 150% (w/v) NaCl had an optimal performance, with a porosity of 78.83%, pore size of 293.25 ± 42.77µm and mechanical strength of 31.03 MPa. Proliferation of human placenta-derived mesenchymal stem cells (hPMSCs) on leaching extract medium was similar to the normal medium (P = 0.89), which was better than that on control group (P = 0.03). Activity of alkaline phosphatase on BCP/rhBMP-2/SF surface was higher than on pure BCP at each time point except at 1 day (P < 0.05). RhBMP-2 has a burst release on early times and a sustaining release on later times. BCP/rhBMP-2/SF with 150% (w/v) pore-forming agent has excellent porosity, pore size and mechanical strength. The biomaterial induces proliferation and differentiation hPMSCs effectively.


Assuntos
Proteína Morfogenética Óssea 2/química , Fosfatos de Cálcio/química , Fibroínas/química , Microesferas , Fator de Crescimento Transformador beta/química , Animais , Materiais Biocompatíveis/química , Bombyx , Osso e Ossos/metabolismo , Adesão Celular , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Durapatita/química , Feminino , Humanos , Cinética , Células-Tronco Mesenquimais/citologia , Microscopia Eletrônica de Varredura , Placenta/metabolismo , Porosidade , Gravidez , Proteínas Recombinantes/química , Cloreto de Sódio/química , Estresse Mecânico , Fatores de Tempo
20.
Mol Nutr Food Res ; 68(4): e2300735, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38227364

RESUMO

SCOPE: Breast milk has the potential to prevent childhood obesity by providing probiotics, but there are still instances of obesity in breastfed children. METHODS AND RESULTS: This study investigates the difference in intestinal flora structure between breastfed children with obesity (OB-BF) and normal-weight breastfed children (N-BF). Building upon this foundation, it employs both cell and mouse models to identify an antiobesity strain within the fecal matter of N-BF children and explore its underlying mechanisms. The results reveal a reduction in lactobacillus levels within the intestinal flora of OB-BF children compared to N-BF children. Consequently, Lactobacillus plantarum H-72 (H-72) is identified as a promising candidate due to its capacity to stimulate glucagon-like peptide-1 (GLP-1) secretion in enteroendocrine cells (ECCs). In vivo, H-72 effectively increases serum GLP-1 concentration, reduces food intake, regulates the expression of genes related to energy metabolism (SCD-1, FAS, UCP-1, and UCP-3), and regulates gut microbiota structure in mice. Moreover, the lipoteichoic acid of H-72 activates toll-like receptor 4 to enhanced GLP-1 secretion in STC-1 cells. CONCLUSIONS: L. plantarum H-72 is screened out for its potential antiobesity effect, which presents a potential and promising avenue for future interventions aimed at preventing pediatric obesity in breastfed children.


Assuntos
Microbioma Gastrointestinal , Obesidade Infantil , Probióticos , Humanos , Criança , Animais , Camundongos , Feminino , Aleitamento Materno , Intestinos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Probióticos/farmacologia
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