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Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.
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@#Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, characterized by highly hypoxic tumor microenvironment. Hypoxia-inducible factor-1α (HIF-1α) is a major regulator involved in cellular response to changes of oxygen levels, supporting the adaptation of tumor cells to hypoxia. Bruceine D (BD) is an isolated natural quassinoid with multiple anti-cancer effects. Here, we identified BD could significantly inhibit the HIF-1α expression and its subsequently mediated HCC cell metabolism. Using biophysical proteomics approaches, we identified inhibitor of β-catenin and T-cell factor (ICAT) as the functional target of BD. By targeting ICAT, BD disrupted the interaction of β-catenin and ICAT, and promoted β-catenin degradation, which in turn induced the decrease of HIF-1α expression. Furthermore, BD could inhibit HCC cells proliferation and tumor growth in vivo, and knockdown of ICAT substantially increased resistance to BD treatment in vitro. Our data highlight the potential of BD as a modulator of β-catenin/HIF-1α axis mediated HCC metabolism.
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COVID-19, an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread throughout the world. China has achieved rapid containment of this highly infectious disease following the principles of early detection, early quarantine and early treatment with integrated traditional Chinese and Western medicine. The inclusion of traditional Chinese medicine (TCM) in the Chinese protocol is based on its successful historic experience in fighting against pestilence. Current findings have shown that the Chinese medicine can reduce the incidence of severe or critical events, improve clinical recovery and help alleviate symptoms such as cough or fever. To date there are over 133 ongoing registered clinical studies on TCM/integrated traditional Chinese and Western medicine. The three Chinese patent medicines (/ (Forsythiae and Honeysuckle Flower Pestilence-Clearing Granules/Capsules), (Honeysuckle Flower Cold-Relieving Granules) and (Stasis-Resolving & Toxin-Removing) were officially approved by the National Medical Products Administration to list COVID-19 as an additional indication. The pharmacological studies have suggested that Chinese medicine is effective for COVID-19 probably through its host-directed regulation and certain antiviral effects.
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Objective To observe the effect of multiple monitoring of total intravenous anes-thesia on postoperative cognitive function in elderly patients.Methods Elective 100 patients undergo-ing general anesthesia for abdominal operation,56 males,44 females,aged 65-80 years,ASA physi-cal status Ⅱ or Ⅲ.All patients were divided into multiple monitoring group (group M)and routine monitoring group (group R)by random digital table method,n =50 each.In group M,the anesthesi-ologists modulated anesthetic drugs to make NTI of 37-56 and rSO 2 higher than 50% or not lower than the baseline value by 20%,while in group R the infusion rate of propofol,remifentanil and cisa-tracurium was adjusted by anesthesiologists according to anesthesiologist’s experiences by the pa-tients’monitoring index.Cognitive function of patients in the two groups were evaluated using MMSE 1 d before surgery and 1 d,3 d,7 d,1 month and 3 months after surgery.The occurrence of cognitive dysfunction 7 d,1 month and 3 months after surgery,the postoperative recovery and the dosage of propofol,remifentanil and cisatracurium were recorded.Blood was randomly selected from each group to determine the serum content of S100βand Aβ1-42 by ELISA method at the time point of before surgery (T0 ),one hour after starting surgery (T1 ),the end of surgery (T2 )and postopera-tive 24 hours (T3 ).Results The incidence of postoperative cognitive decline in group M on 1 d (8%vs.22%),3 d (2% vs.1 6%)after surgery were significantly lower than that in group R (P <0.05). Postoperative cognitive dysfunction between the two groups 7 d and 1 month,3 months after surgery has no statistical significance.The dose of propofol [(3.3 ± 0.8)mg · kg-1 · h-1 vs.(3.7 ± 0.7 ) mg·kg-1 ·h-1 ,P < 0.05 ] and cisatracurium [(104 ± 47 )μg · kg-1 · h-1 vs.(124 ± 68 )μg·kg-1 ·h-1 ,P <0.05]in group M was less than that in group R.The time of eye-opening [(10 ±3)min vs.(1 6±6)min,P <0.01],extubation [(13±3)min vs.(22±7)min,P <0.01]and lo-cation [(1 7±4)min vs.(27 ±9)min,P <0.01 ]was shorter in group M.Compared with T0 ,the serum level of S100βprotein was significantly increased in group M at T1 ,T2 and group R at T1-T3 (P <0.05);The level of serum S100βprotein in group M was significantly lower than that in group R (P <0.05).Compared with T0 ,Aβ1-42 protein level was significantly reduced in two groups at T1 and T2 (P <0.05),but there was no significant difference between the two groups.Conclusion Total intravenous anesthesia with multiple monitoring can reduce neural injury and reduce the incidence of early postoperative cognitive decline in elderly patients with abdominal surgery,but has no significant effect on the incidence of POCD.
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Objective To understand the infection of ureaplasma urealyticum in genitourinary of secondary infertility of male and ex-plore the relationship between the genotype of individual ureaplasma species and genitourinary infection of them . Methods Based on the multiple-banded antigen genes (MBA) of ureaplasma urealyticum, 10 pairs of oligonueleotide primers targeting the 5'ends of the MBA genes were designed to identify the MBA genes of U. parvum and U. ureaplasma by PCR-based genotyping system. The 10 pairs of oligonucleotide primers could distinguish the two biovars and 14 serovars of U. ureaplasma. Results A total of 278 (48.6%) positive ureaplasma culture were obtained from 572 patients attending our clinic of reproductive medical eenter. These methods were used to identify and genotype U. ureaplasma in 311 (54.4%) of 572 patients with genitourinary infection among them U. parvum (biovar 1) was detected in 37.1% and U. ureaplasma (biovar 2) in 17.8%. serovar 1 was in 12.4%, serovars3/14 in 17.1% serovar 6 in 7.5%; subtype 1 of biovar 2 was in 5.6%, subtype 2 in 8.9% and subtype 3 in 2.8%, respectively. Conclusion The PCR-based genotyping system will facilitate future stud-ies of relationship between individual Ureaplasma species or subtypes in genitourinary of secondary infertility of male. The methods described here are relatively rapid, practicable, and specific for the detection species identification and subtyping of Ureaplasma species.
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The immunosuppressive potential of mycophenolic acid (MPA) correlates well with MPA exposure [area under the concentration-time curve (AUC)]. Monitoring MPA AUC is important and helpful for maintaining the efficacy of mycophenolate mofetil while minimizing its side effects, but full MPA AUC monitoring is laborious, cost prohibitive, and impractical. Limited sampling strategies have been proposed as an alternative method for estimating MPA exposure. The objective of this study was to evaluate the practicability of different limited sampling strategies for the estimation of MPA exposure. A total of 56 pharmacokinetic profiles from 53 adult renal recipients were used to evaluate the practicability of 10 published models. Standard correlation and linear regression analysis were used to compare the estimated MPA AUCs and corresponding full MPA AUCs, and the percentage of profiles for which prediction error fell within +/-20% was also used to assess the practicability of these models. Agreement between the estimated MPA AUCs and full MPA AUCs was further tested by Bland and Altman analysis. The model, based on four sampling time points, used the formula AUC = 12.61 + 0.37 x C0.5 + 0.49 x C1 + 3.22 x C4 + 8.17 x C10, was superior to all other evaluated models, with the highest coefficient of determination (r = 0.88), a low percentage prediction error (2.79%), and good agreement according to Bland and Altman analysis. Prediction errors of 87.5% (49/56) of profiles were within 20%, which was the highest of all the models. This algorithm can be reliably used for estimating MPA exposure in adult renal transplant patients treated with cyclosporine as concomitant immunosuppressant. Another model based on the formula AUC = 8.22 + 3.16 x C0 + 0.99 x C1 + 1.33 x C2 + 4.18 x C4 also has acceptable predictive performance, and it may also be practical, especially in outpatient settings, in view of its distribution of time points.
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Monitoreo de Drogas/métodos , Inmunosupresores/farmacocinética , Trasplante de Riñón , Ácido Micofenólico/farmacocinética , Adulto , Algoritmos , Área Bajo la Curva , Pueblo Asiatico , China , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Inmunosupresores/sangre , Masculino , Ácido Micofenólico/sangre , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Mycophenolate mofetil (MMF), the oral prodrug of mycophenolic acid (MPA), is increasingly used in liver transplantation and plays a central role in the immunosuppressive regimen in liver transplantation. To study pharmacokinetic-pharmacodynamic relationships and therapeutic drug monitoring of MPA in the clinical setting, limited sampling strategies have been investigated for the estimation of MPA areas under the curves (AUCs). Thirty-eight adult patients undergoing liver transplant (31 males, seven females) receiving 1.0 g MMF twice daily and concomitant tacrolimus provided a total of 72 pharmacokinetic profiles. Multiple stepwise regression analysis was used to determine the algorithms for limited sampling strategies. Twenty-eight one-, two-, three-, and four-sampling estimation models were fitted (r = 0.288-0.964) to all the profiles using linear regression and were used to estimate MPA AUC0-12h comparing those estimates with the corresponding AUC0-12h values calculated with the linear trapezoidal rule, including all 10 timed MPA concentrations. The four-point estimates at C1h, C2h, C6h, and C8h resulted in the best correlation between estimated AUC and true AUC when using the formula AUC = 6.03 + 0.89C1h + 1.94C2h + 2.24C6h + 4.64 C8h (r = 0.911). Bland and Altman analysis revealed good agreement between estimated AUC and AUC from the full profile. This limited sampling strategy provides an effective approach for estimation of full MPA AUC0-12h in patients undergoing liver transplant receiving concomitant tacrolimus therapy.
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Recolección de Muestras de Sangre/métodos , Monitoreo de Drogas/métodos , Inmunosupresores/farmacocinética , Trasplante de Hígado , Ácido Micofenólico/análogos & derivados , Adulto , Anciano , Área Bajo la Curva , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapéutico , Tacrolimus/farmacocinética , Tacrolimus/uso terapéuticoRESUMEN
AIMS: To characterize the pharmacokinetics of mycophenolic acid (MPA) in Chinese renal transplant patients. METHODS: Thirty-one renal transplant patients (17 male, 14 female) receiving mycophenolate mofetil (MMF) 1.0 g twice daily were included in this study. A pharmacokinetic study was performed during an interval in dosing after steady state had been reached within 2 months after transplantation. The plasma MPA concentration were measured by high-performance liquid chromatography (HPLC) at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software. SAS software was used for statistical analysis. Multiple linear regression analysis was used to determine limited sampling approaches. RESULTS: The mean peak plasma concentration (C(max)) and area under the concentration-time curve (AUC(0-12)) were 19.67 +/- 8.21 microg ml(-1) and 52.16 +/- 12.50 microg h ml(-1), but there was large variability in these pharmacokinetic parameters. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that each of the concentrations at 0.5, 1, 4 and 10 h was positively correlated with AUC (r = 0.60, P = 0.0004; r = 0.60, P = 0.0003; r = 0.61, P = 0.0003; r = 0.64, P = 0.0001, respectively). The combined use of these four samples explained over 90% of the variance in the total (nine-point) AUC(0-12). A formula was obtained for the assessment of MPA AUC based on four samples: MPA AUC = 12.61 + 0.37 x C(0.5) + 0.49 x C(1) + 3.22 x C(4) + 8.17 x C(10). CONCLUSIONS: Chinese renal transplant patients had higher median AUCs than caucasians and African-Americans. As in other studies, there was large interindividual variability. A limited four-point AUC was in good agreement with the 12-h AUC and provided the basis of a predictive formula.
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Inmunosupresores/farmacocinética , Trasplante de Riñón , Ácido Micofenólico/farmacocinética , Adolescente , Adulto , Anciano , Área Bajo la Curva , China , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Ácido Micofenólico/sangre , Resultado del TratamientoRESUMEN
ONYX-015 and H101 are E1B 55-kDa protein-deficient replicating C group adenoviruses that are currently in clinical trials as antitumor agents. However, their application in cancer gene therapy is limited by the native tropism of C group adenoviruses. This is in part due to low expression of the C group adenovirus receptor (coxsackievirus-adenovirus receptor, CAR) on malignant tumors. An H101-based chimeric virus vector containing sequences encoding the Ad35 fiber domain instead of the Ad5 fiber (H101-F35) was constructed. This modification allowed infection of tumor cells through CD46, a membrane protein over-expressed on tumors. The CAR and CD46 RNA expression was evaluated by RT-PCR method. H101-F35 conferred a stronger cytocidal effect than H101 and ONYX-015 in tumor cell lines that lacked CAR expression (MDA-MB-435 and MCF-7), while the cytocidal effect of H101-35, H101 and ONYX-015 was similar in high-level CAR expressing cancer cell lines (A549, NCI-H446, Hep3B, LNCaP, ZR-75-30 and Bcap-37). In an MDA-MB-435 xenograft mouse tumor model, tumor growth in mice receiving H101-F35 was significantly inhibited compared with mice injected with H101. These results suggest that the chimeric oncolytic adenovirus H101-F35 vector might be a useful candidate for gene therapy of cancer.
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Gastroesophageal reflux(GER) has a close association with asthma through vagal nerve.Cholinergic nerve and cholinergic receptors might play an important role in the development of GER-induced asthma,indicating that anti-cholinergic drugs may have therapatic potential in the treatment of asthma induced by gastroesophageal reflux.
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The mechanisms of antidepressants are still unclear. There a re two classical theories on monoamine neurotransmitter or on neurotransmitter rec eptors, but both of them can not fully explain the delayed therapeutic action of antidepressants. Recently, many researches have focused on the postreceptor int racellular signal transduction as the mechanism of antidepressant action. G protein is the molecular basis of antidepressants. Neurotransmitter receptors and G protein are the two sectors of their therapeut ic action. They will ultimately influence intracellular signal transduction and result in relative effects such as phosphoration, the induction of neurotrophic factors and neurogenesis. This mechanism suggests a reasonable explanation for t he clinical delaying of antidepressants and it will do great help for the develo pment of antidepressants. It makes the design of novel, safe and more efficaciou s antidepressants possible and provides significant information for the elucidat ion of biology of depression.
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G protein-coupled receptors(GPCRs)mediate cell signaling transduction of most hormones and neurological transmitters and behave as the key targets for drug research and development.Recently,the evidence of allosteric modulation of GPCRs has been revealed.Allosteric modulators have the ability to selectively tune responses only in tissues in which the endogenous agonist exerts its physiological effects,and have the potential for greater receptor subtype selectivity.The GPCRs allosteric modulators have been found and some of them have been in clinical use.Under the strategy of allosterism on structure activity relationship and target directed screening,more and more GPCRs allosteric modulators will be developed in the future.
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Lipoxygenase(LO) pathway had been implicated in the pathogenesis of such cardiovascular diseases as hypertension, atherosclerosis, restenosis, and palys and important role in the development of these disease. LO inhibitiors could suppress vascular contractile responses significantly, reduce blood pressure, inhibit migration of vascular smooth muscle cells(VSMC), attenuate neointimal thickening in the injuried arteries and generation reactive oxygen species(ROS), block monocyte binding to VSMC, etc. The effects of LO inhibitors were associated with marked inhibition of MAPK pathway. Therefore, inhibition of LO pathway may provide a new strategy for preventing and treating above diseases, suggesting that LO mat be a novel taget for such purposes.
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Aim To investigate the protective effects of high concentration fentanyl on the brain slice injury induced by oxygen glucose deprivation(OGD).Methods Rat brain slices were made and randomly assigned to four groups:control(n=10),OGD(n=10),fentanyl 50 ?g?L~(-1)(F_(50),n=10) and fentanyl 500 ?g?L~(-1)(F_(500),n=10).Changes of the neuron injury and apoptosis were observed with TTC staining,LDH releases,TUNEL staining,immunohistochemistry and electromicroscope.In addition,changes of intracellular calcium were measured with confocal laser-scanning microscopy.Results F_(50) and F_(500) attenuated the decrease of TTC staining and the increase of LDH release induced by OGD in brain slices.Neuronal apoptosis and changes of neuronal ultrastructures were attenuated by F_(50) and F_(500).Bcl-2 and Bax protein expressions were increased after OGD.Bax protein expression was decreased by F_(50) and F_(500),while Bcl-2 protein expression was increased by F_(50)and F_(500).Intracellular calcium concentration was increased by OGD and then it was lowered by F_(50) and F_(500).The protective effects of F_(50) were more obvious than that of F_(500).Conclusions High concentrations of fentanyl have neuron protective effects against OGD injury in rat brain slices,and fentanyl 50 ?g?L~(-1) has more obvious protective effects than fentanyl 500 ?g?L~(-1).
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Nerve growth factor (NGF), one of the most potent growth factors for cholinergic neurons, has generated great interest as a potential target for the treatment of Alzheimers disease (AD). The degeneration of basal forebrain cholinergic neurons, which provides the major source of cholinergic innervation to the cerebral cortex and hippocampus, occurs early and contributes significantly to cognitive decline in AD. Those regions show high level expression of NGF and NGF receptors and depend on NGF for their survival and proper function. NGF executes its effects mainly by binding high affinity receptor TrkA in the remaining neurons of AD. Meanwhile, stimulation of neurons may protect those cells from the deleterious effects of AD, a phenomenon called “use it or lose it.”However, the use of NGF as therapeutic agent is limited by their hindered mobility through the blood brain barrier. Many theoretical and technical issues for NGF delivery to the target region in the brain remain to be solved, before NGF can live up to its potential for the treatment of AD.
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AIM: To investigate the enhancement of ethanol on percutaneous permeation and topical anaesthesia of tetracaine gel. METHODS: Tetracaine (4%, w/w) gels were prepared by using 20% and 70% ethanol as penetration enhancers. Franz diffusion chamber and UV spectrophotometry were adopted in the transdermal osmotic test of isolated mouse skin. Von Frey test was used to evaluate the topical anesthetic effect of tetracaine gels. RESULTS: 20% and 70% ethanol greatly improved the percutaneous permeation of tetracaine gel (P
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AIM To study the effect of desipramin e (DMI) on proliferation inhibition and apoptosis induction of rat glioma C6 cel ls. METHODS Cell proliferation w as measured by MTT colorimetric assay and cells undergoing apoptosis were determ ined by electron microscope and flow cytometry. The expression of bcl-2 was eva luated by immunohistochemistry. RESULTS DMI could result in the c oncentration-dependent inhibition of C6 cell proliferation and lead to arrest i n G0~G1 phase of cell cycle. The value of IC50 and 95% confidence lim its were 20.7(17.3~24.2) μmol*L-1.DMI(40 μmol*L-1)-indu ced apoptosis showed classical apoptotic morphology and the hypodiploid peak ap peared on the histogram of FCM in a concentration-dependent manner, which could be abrogated by cycloheximide(1.8 μmol*L-1). Meanwhile, DMI (10 μmol *L-1) could down-regulate the expression of apoptosis associated gene b cl-2. CONCLUSION DMI could inhibit cell proliferation in a con centration dependent manner and induce typical apoptosis of C6 cells.
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Platelet-activating factor (PAF), an endogenous bioactive lipid generated by phospholipase A2 and other pathways, displays a variety of biological activities in the nervous system. It has been suggested that PAF plays important roles in neuronal physiological functions including acting as a retrograde messenger to enhance synapse plasticity and memory formation, via activation of its specific membrane receptors.Therefore,the drugs that mimic the action of PAF or modulate the production and inactivation of PAF maybe promising in memory-enhancing. However, under certain pathological conditions, such as Alzheimer's disease, HIV-associated dementia or post-ischemic neuronal death, acting as a potent inflammatory mediator and neurotoxin, PAF has been implicated in the pathophysiology of brain injury. So, modulating the metabolism and effects of PAF (e.g., blocking the PAF receptor) may become important strategies of intervention of Alzheimer's disease, HIV-associated dementia or post-ischemic neuronal death.
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Objective To investigate the neuroprotective effect of panaxynol on primary cultured cortical neuron against oxidative stress. Methods Viability of panaxynol acted on neuron oxidative stress was monitored by MTT assay and FCM method. Scavenging effects of panaxynol on free radicals were observed in vitro. Effects of panaxynol on SOD activity and GSH-Px, and MDA content in primary neuron injured by H_2O_2 were also determined. Results Panaxynol (2—16 ?mol/L) could dose-dependently protect neuron from oxidative stress induced by H_2O_2; 8 ?mol/L of panaxynol could decrease necrosis and apoptosis rate of neuron significantly (P