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1.
Eur J Pharm Sci ; : 105724, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33482315

RESUMO

BACKGROUND: Ammoxetine is a novel selective serotonin and norepinephrine reuptake inhibitor. Preclinical studies have indicated the potential utility of ammoxetine for therapy in major depressive disorder. PURPOSE: To investigate the first-in-human safety, tolerability, and pharmacokinetics (PK) of ammoxetine in healthy subjects and evaluate the effect of CYP2C19 polymorphisms on metabolism of ammoxetine. METHODS: In this randomized, double-blind, placebo-controlled phase I study, healthy Chinese subjects were allocated to receive 2.5, 7.5, 15, 30, 45, 65, 100 mg ammoxetine or placebo in single-dose part and 15, 30, 45 mg ammoxetine or placebo twice daily for 8 days in multiple-dose part. Pharmacokinetic, safety and tolerability assessments were performed. RESULTS: A total of 134 subjects were screened and 94 were enrolled. All the ammoxetine-related adverse events (AEs) were mild and resolved spontaneously. No hepatic AEs were reported during the study. Ammoxetine was well absorbed after oral administration with Tmax reached in 5.0-6.0 h. After single-dosing, Cmax and AUC increased proportionally with dose, except at 65 mg. After multiple-dosing, the exposures of ammoxetine at steady state increased slightly in a more-than-dose-proportional manner over the dose range studied, probably due to the saturated elimination. Steady state was achieved 6 days after multiple-dosing was initiated. The low extent of urinary excretion of ammoxetine (< 2%) indicated it is undergoing extensive metabolism. CYP2C19 polymorphisms had minimal effect on metabolism of ammoxetine. CONCLUSIONS: Ammoxetine has a favorable pharmacokinetic profile after oral administration and good safety properties. The PK and safety profiles of ammoxetine could enable further clinical development in patients with major depressive disorder.

2.
Hum Reprod ; 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33279973

RESUMO

STUDY QUESTION: Is there an association between the human testis-specific gene, testis developmental related gene 1 (TDRG1) and human sperm motility? SUMMARY ANSWER: TDRG1 is associated with asthenozoospermia and involved in regulating human sperm motility. WHAT IS KNOWN ALREADY: Many testis-specific proteins potentially regulate spermatogenesis and sperm motility. We have identified a novel human testis-specific gene, TDRG1, which encodes a 100-amino-acid protein localized in the human sperm tail, yet little is known about its role in human spermatozoa. STUDY DESIGN, SIZE, DURATION: Sperm samples were obtained from normozoospermic men and asthenozoospermic men who visited the reproductive medical center at Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China between February 2018 and January 2019. In total, 27 normozoospermic men and 25 asthenozoospermic men were recruited to participate in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The level of TDRG1 in sperm of normozoospermic and asthenozoospermic men was examined by immunoblotting and immunofluorescence assays. Progressive motility was examined by computer-aided sperm analysis. The correlation between the TDRG1 protein level and progressive motility was analyzed by linear regression. TDRG1 was imported into the sperm of normozoospermic and asthenozoospermic men using a cell-penetrating peptide (CPP)-fused TDRG1 recombinant protein (CPP-TDRG1), and the progressive motility was examined. Also, the altered proteins associated with TDRG1 in asthenozoospermic sperm were detected using label-free quantification method-based quantitative proteomic technology. TDRG1-interacting proteins were identified by co-immunoprecipitation coupled with tandem mass spectrometry analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The mean level of TDRG1 was significantly decreased in sperm of asthenozoospermic men compared with normozoospermic men (P < 0.05) and was positively correlated with percentage of progressively motile sperm (r2 = 0.75, P = 0.0001). The introduction of TDRG1 into human sperm, using CPP, significantly increased progressive motility (P < 0.05) and improved the progressive motility of sperm from asthenozoospermic men to the normal level. TDRG1 forms a protein complex with sperm-motility related proteins in human sperm and its downregulation was associated with a decrease in other motility-related proteins. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The sample size was limited and larger cohorts are needed for verifying the positive effect of CPP-TDRG1 on human sperm motility. Furthermore, the caution should be paid that a comprehensive safety examination would be performed to evaluate whether CPP-TDRG1 is a possible treatment approach for asthenozoospermia. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide new insights into the mechanisms of sperm motility which may contribute to the diagnosis and treatment for asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S): National Natural Science Foundation of China (81501317 and 81871207 to H.C.; 81771644 to T.L.; 31671204 to X.Z.; 81571432 to Y.T.). The authors have no conflicts of interest to declare.

3.
Pain Res Manag ; 2020: 5626948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376567

RESUMO

Background: Hong-Hui-Xiang (HHX) is a sterilized aqueous solution extracted from Illicium lanceolatum A.C. Smith widely used for pain relief in China. Despite its history, it is not well understood. In the present study, we used a mouse model of arthritic knee pain to investigate the antinociceptive effects of HHX and its potential side effects on weight and respiratory function, as well as on the liver, kidney, and heart. Methods: Mice were randomly assigned to four groups: saline and HHX at three doses (1 µl, 10 µl, and 50 µl). Each group was randomly divided to two subgroups: saline and CFA. After the first injection of HHX or saline on day 7, mechanical hyperalgesia was tested via the hind paw. Only after the tests had established that the analgesic effect had subsided was the next injection administered. A total of five injections were administered. Blood, knee joints, and other organs were collected for histopathological observation and biochemical detection. Objectives: We found that mechanical threshold of hind paw increased 2 h after of the initial injection HHX (10 µl and 50 µl), which lasted for at least 3 h. The analgesic effect lasted for three days after the second injection on day 8 and was approximately maintained for five days each time after the third injection. We also found a reduction in the diameter of the knee joint and suppression of synovial inflammation in response to treatment of HHX (10 µl and 50 µl). Meanwhile, HHX had no toxic effects on the liver, kidneys, and heart via histological and biochemical assays in all groups. Conclusion: HHX exerts antinociceptive and anti-inflammatory effects in a mouse model of arthritic knee pain. There were no obvious side effects on the liver, kidneys, or heart.

4.
Mol Med ; 26(1): 105, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33167857

RESUMO

BACKGROUND: Acupuncture treatment possesses the neuroprotection potential to attenuate cerebral ischemia-reperfusion (I/R) injury. Endoplasmic reticulum (ER) stress has been suggested to be involved in the pathogenic mechanism of cerebral I/R injury. Whether acupuncture protects against cerebral I/R injury via regulating ER stress remains unclear. This study aimed to evaluate the role of ER stress in the neuroprotection of acupuncture against cerebral I/R injury and its underlying mechanisms. METHODS: Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) in rats. Acupuncture was carried out at Baihui (GV 20), and Qubin (GB7) acupoints in rats immediately after reperfusion. The infarct volumes, neurological score, ER stress, autophagy and apoptosis were determined. RESULTS: Acupuncture treatment decreased infarct volume, neurological score and suppressed ER stress via inactivation of ATF-6, PERK, and IRE1 pathways in MCAO rats. Attributing to ER stress suppression, 4-PBA (ER stress inhibitor) promoted the beneficial effect of acupuncture against cerebral I/R injury. Whereas, ER stress activator tunicamycin significantly counteracted the neuroprotective effects of acupuncture. In addition, acupuncture restrained autophagy via regulating ER stress in MCAO rats. Finally, ER stress took part in the neuroprotective effect of acupuncture against apoptosis in cerebral I/R injury. CONCLUSIONS: Our findings suggest that acupuncture offers neuroprotection against cerebral I/R injury, which is attributed to repressing ER stress-mediated autophagy and apoptosis.

5.
Cell Death Dis ; 11(10): 934, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127884

RESUMO

Acute respiratory distress syndrome (ARDS) is common in intensive care units (ICUs), although it is associated with high mortality, no effective pharmacological treatments are currently available. Despite being poorly understood, the role of programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) axis in ARDS may provide significant insights into the immunosuppressive mechanisms that occur after ARDS. In the present study, we observed that the level of soluble PD-L1 (sPD-L1), a potential activator of the PD-1 pathway, was upregulated in survivors of direct ARDS than in non-survivors. Administration of sPD-L1 in mice with direct ARDS relieved inflammatory lung injury and improved the survival rate, indicating the protective role of sPD-L1 in direct ARDS. Using high-throughput mass cytometry, we found a marked decrease in the number of lung monocyte-derived macrophages (MDMs) with proinflammatory markers, and the protective role of sPD-L1 diminished in ARDS mice with monocyte/macrophage depletion. Furthermore, PD-1 expression increased in the MDMs of patients and mice with direct ARDS. Finally, we showed that sPD-L1 induced MDM apoptosis in patients with direct ARDS. Taken together, our results demonstrated that the engagement of sPD-L1 on PD-1 expressing macrophages resulted in a decrease in pro-inflammatory macrophages and eventually improved direct ARDS. Our study identified a prognostic indicator for patients with direct ARDS and a potential target for therapeutic development in direct ARDS.

6.
Sci Rep ; 10(1): 12375, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704066

RESUMO

ß-Cyclodextrin (ß-CD) inclusion complex containing geranyl acetone as a guest was prepared by saturated water solution method. Furthermore, the structure and properties of the inclusion complex were studied. The formation of the inclusion complex was demonstrated by. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (X-RD), thermogravimetric analysis (TG) and differential scanning calorimetry (DSC). The thermodynamic analysis of the inclusion complex showed that the inclusion reaction is an endothermic spontaneous reaction. The average of △H, △S and △G is 11.66 kJ mol-1, 0.082 kJ mol-1 and - 14.49 kJ mol-1, respectively. Moreover, the kinetic analysis of thermal decomposition of the inclusion compound showed that the thermal decomposition reaction is a first-order reaction (the inclusion ratio is 1:1), the average activation energy of the reaction is 180.90 kJ mol-1, and the binding force in the inclusion compound is mainly Van der Waals force. The flavor test of cigarettes showed that the inclusion compound improved the stability of geranyl acetone and the sensory quality of cigarettes. This study improves the solubility and thermal stability of geranyl acetone, and provides theoretical support and technical guidance for expanding the application of geranyl acetone.

7.
Respir Res ; 21(1): 99, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32354336

RESUMO

BACKGROUND: There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model. METHODS: Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder. RESULTS: The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. CONCLUSION: Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4.

8.
Dev Comp Immunol ; 109: 103691, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32251698

RESUMO

An 8-week feeding trail was conducted in Acanthopagrus schlegelii with an initial body weight of 8.34 ± 0.01g. Three isonitrogenous diets were formulated, (1) Control: medium-fat diet (12%); (2) HFD: high-fat diet (18%); (3) HFD + FF: high-fat diet with fenofibrate (0.15%). Liver histological analysis revealed that, compared to HFD, vacuolar fat drops were smaller and fewer in fish fed fenofibrate. Expression of lipid catabolism regulator peroxisome proliferator-activated receptor alpha (pparα) was up-regulated by fenofibrate compared with HFD. In addition, fenofibrate significantly increased the expression level of silent information regulator 1 (sirt1). Meanwhile, the expression level of anti-inflammatory cytokine interleukin 10 (il-10) in intestine was up-regulated, while pro-inflammatory cytokine interleukin 1ß (il-1ß) in liver and intestine were down-regulated by dietary fenofibrate supplementation. Overall, the present study indicated that fenofibrate reduced fat deposition and attenuated inflammation response caused by HFD partly through a pathway involving regulation of pparα and sirt1.

9.
J Alzheimers Dis ; 75(1): 245-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280096

RESUMO

Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer's disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+, Parvalbumin+, Calretinin+, and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-ß accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy.

10.
Crit Rev Oncol Hematol ; 150: 102944, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32247246

RESUMO

BACKGROUND: Graft-versus-host disease (GVHD) is a leading cause of death in patients after hematopoietic stem-cell transplantation (HSCT). Previous studies have shown different efficacy of GVHD prophylaxis therapies. METHODS: We reviewed 46 randomized controlled trials (including 8050 participants) systematically from Jun 20, 2004 to Aug 20, 2019. These investigations compared the following drugs or their combination at therapeutic dose range for GVHD after HSCT. The main results were based on the proportion of patients who respond to these therapies. RESULTS: Cyclosporine + methotrexate + Anti-T cell globulin (ATG), tacrolimus + methotrexate + ATG, tacrolimus + bortezomib + sirolimus and cyclosporine + marrow mesenchymal stem cells (MMSCs) were significantly more efficacious than corticosteroids alone (OR: 12.15, 6.71, 6.25, 3.73). corticosteroids alone were less efficacious than all the other GVHD prophylaxis therapies tested. CONCLUSION: Cyclosporine + methotrexate + ATG may be the best choice when starting treatment for GVHD.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Bortezomib/uso terapêutico , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Doença Enxerto-Hospedeiro/imunologia , Humanos , Metotrexato/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Transplante Homólogo , Resultado do Tratamento
11.
Mol Ther Nucleic Acids ; 19: 1434-1448, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32160712

RESUMO

Drug resistance, including adriamycin (ADR)-based therapeutic resistance, is a crucial cause of chemotherapy failure in breast cancer treatment. Acquired chemoresistance has been identified to be closely associated with the overexpression of P-glycoprotein (P-gp/ABCB1). Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) can be involved in carcinogenesis; however, its roles in ABCB1-mediated ADR resistance are poorly understood. In this study, we identified a panel of differentially expressed lncRNAs, mRNAs, and microRNAs (miRNAs) in MCF-7 and MCF-7/ADR cell lines through RNA sequencing (RNA-seq) technologies. GAS5 level was downregulated whereas ABCB1 level was upregulated in the resistant breast cancer tissues and cells. Overexpression of GAS5 significantly enhanced the ADR sensitivity and apoptosis, and it inhibited the efflux function and expression of ABCB1 in vitro, while knockdown of GAS5 had the opposite effects. Further mechanism-related investigations indicated that GAS5 acted as an endogenous "sponge" by competing for miR-221-3p binding to regulate its target dickkopf 2 (DKK2), and then it inhibited the activation of the Wnt/ß-catenin pathway. Functionally, GAS5 enhanced the anti-tumor effect of ADR in vivo. Collectively, our findings reveal that GAS5 exerted regulatory function in ADR resistance possibly through the miR-221-3p/DKK2 axis, providing a novel approach to develop promising therapeutic strategy for overcoming chemoresistance in breast cancer patients.

12.
Hum Reprod ; 35(3): 494-503, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32142584

RESUMO

STUDY QUESTION: Does lysine 2-hydroxyisobutyrylation, a newly identified protein posttranslational modification (PTM), occur in human sperm and affect human sperm function? SUMMARY ANSWER: Lysine 2-hydroxyisobutyrylation mainly occurs in human sperm tail proteins, and excessive lysine 2-hydroxyisobutyrylation affects human sperm motility. WHAT IS KNOWN ALREADY: PTM is regarded as an important pathway in regulating sperm function since mature sperm are almost transcriptionally silent. However, only phosphorylation was extensively studied in mature sperm to date. Lysine 2-hydroxyisobutyrylation, a newly characterised PTM, is broadly conserved in both eukaryotic and prokaryotic cells. Although histone lysine 2-hydroxyisobutyrylation has been shown to be associated with active gene expression in spermatogenic cells, the presence, regulatory elements and function of lysine 2-hydroxyisobutyrylation have not been characterised in mature sperm. STUDY DESIGN, SIZE, DURATION: Sperm samples were obtained from normozoospermic men and asthenozoospermic men who visited the reproductive medical centre at Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi, China, between May 2017 and November 2018. In total, 58 normozoospermic men and 65 asthenozoospermic men were recruited to participate in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Lysine 2-hydroxyisobutyrylation was examined using immunoblotting and immunofluorescence assays using a previously qualified pan anti-lysine 2-hydroxyisobutyrylation antibody. The immunofluorescence assay was imaged using super-resolution structured illumination microscopy. Sperm viability was examined by using the eosin staining method, and sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm penetration ability was determined by evaluating the ability of the sperm to penetrate a 1% (w/v) methylcellulose solution. The level of intracellular adenosine triphosphate (ATP) was detected using a rapid bioluminescent ATP assay kit. MAIN RESULTS AND THE ROLE OF CHANCE: Lysine 2-hydroxyisobutyrylation was present in several proteins (20-100 kDa) mainly located in the tail of human sperm. Sperm lysine 2-hydroxyisobutyrylation was derived from 2-hydroxyisobutyrate (2-Hib) and was regulated by acyltransferase P300 and nicotinamide adenine dinucleotide-dependent lysine deacylase sirtuins. Elevation of sperm lysine 2-hydroxyisobutyrylation by 2-Hib decreased total motility, progressive motility, penetration ability and ATP level of human sperm. Interestingly, the level of sperm lysine 2-hydroxyisobutyrylation was higher in asthenozoospermic men than that in normozoospermic men and was negatively correlated with the progressive motility of human sperm. Furthermore, high levels of lysine 2-hydroxyisobutyrylation in asthenozoospermic men accompanied decreased ATP levels. LIMITATIONS, REASONS FOR CAUTION: Although the present study indicated the involvement of sperm lysine 2-hydroxyisobutyrylation in regulating human sperm motility, the underlying mechanism needs to be further illustrated. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study provide insight into the novel role of lysine 2-hydroxyisobutyrylation in human sperm and suggest that abnormality of sperm lysine 2-hydroxyisobutyrylation may be one of the causes for asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S): National Natural Science Foundation of China (81771644 to T.L. and 81871207 to H.C.); Natural Science Foundation of Jiangxi province (20171ACB21006). The authors have no conflicts of interest to declare.

13.
J Affect Disord ; 266: 243-251, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056884

RESUMO

BACKGROUND: Subthreshold depression (StD) is a prevalent condition that may increase the risk of incident major depressive disorder (MDD). However, the relationship between StD and MDD remains unclear. METHODS: A total of 153 adult subjects, including 53 drug-naive MDD, 50 StD and 50 healthy control (HC) subjects, underwent a T1-weighted magnetic resonance imaging scan, and the gray matter volume (GMV) alterations among the three groups were quantitatively analyzed using voxel-based morphometry (VBM). Then, to capture the whole-brain connectivity characteristics, we constructed morphological brain networks (MBN) based on the similarity among brain regions of individual VBM images and compared the network connection strengths among the three groups. RESULTS: The StD and MDD subjects had similar patterns of GMV reductions in the orbitofrontal cortex and left temporal gyrus, although the magnitude of the reductions was smaller in StD subjects. Moreover, a total of 21 morphological connections were significantly different among the three groups. For the majority of the different connections (15/21), the connection strength of the StD group took an intermediate position between that of the MDD and HC groups. LIMITATIONS: There is still a lack of a consistent definition of StD, and the age range of the subjects in this study was wide. Meanwhile the mechanisms and biological significance of the MBN remains to be clarified. CONCLUSIONS: These results may support the hypothesis that depression is better expressed as a spectrum and that StD exists on a spectrum with MDD.

14.
Reprod Fertil Dev ; 32(6): 629-636, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32027815

RESUMO

Di-2-ethylhexyl phthalate (DEHP), a plastic-derived, endocrine-disrupting chemical, has been shown to exhibit male reproductive toxicity. However, its effects on human mature spermatozoa are largely unknown. In this study we investigated the invitro effects of DEHP and mono-2-ethylhexyl phthalate (MEHP; the main metabolite of DEHP) on sperm function and the mechanisms involved. Human spermatozoa were exposed to phthalates invitro at the doses that cover the concentrations detected in human semen: 20nM-8 µM DEHP, 1nM-20 µM MEHP or a mixture of 20nM-8 µM DEHP and 1nM-20 µM MEHP. DEHP and MEHP, alone or in combination, had no effect on the viability, membrane integrity, motility, homeostasis of reactive oxygen species or mitochondrial activity of human spermatozoa. Interestingly, 1nM-20 µM MEHP and combinations of 20nM-8 µM DEHP and 1nM-20 µM MEHP enhanced penetration ability, hyperactivation and the spontaneous acrosome reaction of human spermatozoa, and increased intracellular free Ca2+ concentrations ([Ca2+]i) and tyrosine phosphorylation, two key signalling pathways that regulate sperm function. The findings of this study suggest that invitro exposure to MEHP metabolised from DEHP affects human sperm function by inducing increases in sperm [Ca2+]i and tyrosine phosphorylation, which adds to our understanding of the effects of DEHP on male reproduction.

15.
Andrology ; 8(3): 663-670, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31944615

RESUMO

BACKGROUND: Metformin, a drug used to treat type 2 diabetes, has gained attention for its multiple therapeutic applications. However, little is known about its effects on human sperm function at therapeutically relevant concentration. OBJECTIVES: The aim of this study was to elucidate the in vitro actions of metformin on human sperm function and explore the underlying mechanism of any effects. MATERIALS AND METHODS: Human ejaculated spermatozoa were treated with therapeutically relevant concentrations (0.25, 5, 10, 20, 40, and 80 µM) of metformin in vitro. Fertilization-essential functions of spermatozoa were examined, including viability, motility, capacitation, acrosome reaction, hyperactivation, and penetration ability. The signaling pathways mediated by 5'-AMP-activated protein kinase (AMPK), intracellular calcium concentration ([Ca2+ ]i ), and tyrosine phosphorylation of spermatozoa were also measured. RESULTS: Although metformin did not affect sperm viability, motility, and [Ca2+ ]i , it significantly increased the percentages of capacitated spermatozoa, acrosomal-reacted spermatozoa, and hyperactivated spermatozoa as well as penetration ability of human spermatozoa at the concentrations of 40 and 80 µM (P < .05). These concentrations of metformin also elevated the levels of phosphorylated AMPK and tyrosine phosphorylation in human spermatozoa. In addition, activation of AMPK by A769662 (an AMPK activator) had similar effects to metformin on human spermatozoa, while inhibition of AMPK by Compound C (an AMPK inhibitor) suppressed the enhancement of metformin on human spermatozoa. CONCLUSION: Our findings indicate that metformin activates human sperm function through an AMPK-related mechanism which increases tyrosine phosphorylation at therapeutically relevant concentrations, thereby suggesting its improvement on human sperm function when treating subfertile males of type 2 diabetes.

16.
Neurosci Lett ; 717: 134699, 2020 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-31874218

RESUMO

Extracellular accumulation of amyloid-beta peptides and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins are the two cardinally pathological hallmarks of Alzheimer's disease (AD). However, their exact roles in the mechanisms of AD progression are not well established. Given that AD is a disconnection syndrome and hypometabolism is one of its most important neurodegenerative indicators, we hypothesized amyloid-beta and tau burden may disturb the glucose metabolic network of AD. Here we investigated the relationship of these two factors to regional metabolic network properties using multimodal positron emission tomography (PET) imaging data. Participants included six groups covering from cognitively normal controls, patients with early cognitive impairment (MCI), late MCI, mild AD, moderate AD to severe AD who underwent amyloid-beta PET, tau PET and fluorodeoxyglucose (FDG) PET. Glucose metabolic network of each group was constructed and relations of amyloid-beta and tau to regional metabolic network measurements were investigated. Results revealed distinct associations of these two hallmarks to metabolic networks: amyloid-beta were positively related to metabolic network measurements at relative early phases of AD, while tau burden showed a negative relationship at late phase of AD. These results supported the notion that amyloid-beta and tau accumulation may contribute independently to mechanisms of AD. Furthermore, these findings might also provide connectivity evidence for the speculation that amyloid-beta deposition is protective to neuronal activity.


Assuntos
Doença de Alzheimer/metabolismo , Glucose/metabolismo , Redes e Vias Metabólicas/fisiologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo
17.
Environ Sci Pollut Res Int ; 27(6): 5981-5992, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863371

RESUMO

Senna alexandrina is traditionally used for its antioxidant and anti-inflammatory properties, but little information is available concerning its potential protective effects against cadmium, which is a widespread environmental toxicant that causes hepatotoxicity. Here, we explored the effects of S. alexandrina extract (SAE) on cadmium chloride (CdCl2)-induced liver toxicity over 4 weeks in rats. Rats were allocated into four groups: control, SAE (100 mg/kg), CdCl2 (0.6 mg/kg), and SAE + CdCl2, respectively. Cadmium level in hepatic tissue, blood transaminases, and total bilirubin as indicators of liver function were assessed. Oxidative stress indices [malondialdehyde (MDA), nitrate/nitrite (NO), and glutathione (GSH)], antioxidant molecules [superoxide dismutase (SOD, catalase (CAT), glutathione-derived enzymes, and nuclear factor erythroid 2-related factor 2 (Nrf2)], pro-inflammatory mediators [interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α)], apoptosis proteins (Bcl-2, Bax, and caspase-3), and histological alterations to the liver were examined. SAE administration before CdCl2 exposure decreased cadmium deposition in liver tissue and the blood liver function indicators. SAE pre-treatment prevented oxidative, inflammatory, and apoptotic reactions and decreased histological alterations to the liver caused by CdCl2 exposure. SAE can be used as a promising protective agent against CdCl2-induced hepatotoxicity by increasing Nrf2 expression. Graphical abstract.


Assuntos
Cloreto de Cádmio/toxicidade , Substâncias Perigosas/toxicidade , Substâncias Protetoras/farmacologia , Extrato de Senna/farmacologia , Senna (Planta) , Animais , Antioxidantes , Apoptose , Cádmio , Suplementos Nutricionais , Fígado , Estresse Oxidativo , Ratos , Senosídeos , Superóxido Dismutase
18.
Curr Alzheimer Res ; 16(11): 1055-1062, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31724513

RESUMO

BACKGROUND: Visuospatial dysfunction is one predominant symptom in many atypical Alzheimer's disease (AD) patients, however, until now its neural correlates still remain unclear. For the accumulation of intracellular hyperphosphorylated tau proteins is a major pathogenic factor in neurodegeneration of AD, the distributional pattern of tau could highlight the affected brain regions associated with specific cognitive deficits. OBJECTIVE: We investigated the brain regions particularly affected by tau accumulation in patients with visuospatial dysfunction to explore its neural correlates. METHODS: Using 18F-AV-1451 tau positron emission tomography (PET), voxel-wise two-sample t-tests were performed between AD patients with obvious visuospatial dysfunction (VS-AD) and cognitively normal subjects, AD patients with little-to-no visuospatial dysfunction (non VS-AD) and cognitively normal subjects, respectively. RESULTS: Results showed increased tau accumulations mainly located in occipitoparietal cortex, posterior cingulate cortex, precuneus, inferior and medial temporal cortex in VS-AD patients, while increased tau accumulations mainly occurred in the inferior and medial temporal cortex in non VS-AD patients. CONCLUSION: These findings suggested that occipitoparietal cortex, posterior cingulate cortex and precuneus, which were particularly affected by increased tau accumulation in VS-AD patients, may associate with visuospatial dysfunction of AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Proteínas tau/análise , Idoso , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons
19.
Eur J Med Chem ; 183: 111709, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581004

RESUMO

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (-)-4i induced cell apoptosis and reduced phosphorylation of EGFR and AKT in a dose-dependent manner. Furthermore, (-)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t1/2 = 1.12 h) of (-)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (-)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (-)-4i warrants further investigation in Non-Small cell lung cancer (NSCLC) therapy.


Assuntos
Acrilamidas/química , Compostos de Anilina/química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Animais , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacocinética
20.
Semin Thromb Hemost ; 45(8): 767-777, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31627217

RESUMO

Defibrotide has been approved in several geographic jurisdictions for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) for years. However, available data on efficacy and safety for its use in VOD are contrasting. We performed a meta-analysis to evaluate the efficacy and safety of defibrotide in the treatment of hepatic VOD/SOS post-hematopoietic stem cell transplantation (HSCT). PubMed and Embase were searched for studies regarding the efficacy and safety of defibrotide in VOD patients. Survival rate at day + 100 post-HSCT (D + 100 SR), as well as the prognosis, comprising complete response (CR), adverse events including ≥1 adverse event (≥1 AE), hemorrhage, and serious adverse events (SAEs), were pooled using a random effect model. Sixteen studies involving 3,002 participants were included. Pooled estimates for overall D + 100 SR as well as rate of CR, ≥1 AE, hemorrhage, SAEs in VOD patients post-HSCT were 58% (95% CI: 54-62%), 57% (95% CI: 45-68%), 65% (95% CI: 54-75%), 16% (95% CI: 5-27%), 53% (95% CI: 51-55%), respectively, and were 44% (95% CI: 39-48%), 39% (95% CI: 28-50%), 88% (95% CI: 71-100%), 42% (95% CI: 30-55%), 58% (95% CI: 52-64%), respectively, in severe VOD (sVOD) patients. Hemorrhage and hypotension were the most common AEs. Current evidence suggests that defibrotide improves the D + 100 SR and CR in VOD/sVOD patients following HSCT. However, the results of this review/meta-analysis were mainly based on data from observational studies, potentially subject to selection bias. Consequently, higher quality randomized control trials and larger prospective cohort studies are warranted.


Assuntos
Fibrinolíticos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Fibrinolíticos/farmacologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polidesoxirribonucleotídeos/farmacocinética , Adulto Jovem
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