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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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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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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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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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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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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 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
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Objective To investigate the protective effects of etomidate on the cortex and hippocampus against anoxia-reoxygenation (A/R) injury.Methods Male adult SD rats weighing 90-100 g were anesthetized with ether and decapitated. Their brains were immediately removed. Cortical and hippocampal slices were prepared and were randomly divided into 6 groups: group Ⅰ control; groupⅡ A/R; in group Ⅲ - Ⅵ the brain slices were first incubated in the presence of etomidate 3, 6, 15 ?mol?L-1 or etomidate 6 ?mol?L-1 + picrotoxin 50 ?mol?L-1 (GABA receptor antogonist) for 30 min. Then the slices were subjected to 10 min anoxia (95% N2 +5% CO2) followed by 120 min reoxygenation. The absorbance value (A490) of TTC staining (2. 3. 5-triphenyl tetrazolum chloride) and intracellular free Ca2+ ([Ca2+]i) accumulation were determined. Results The A490 in cortical and hippocampal slices were significantly decreased while [Ca2+] i significantly increased in A/R group as compared with control group. Different concentrations of etonlidate attenuated the changes induced by A/R especially 6 ?mol?L-1. The protective effects of etomidate could be antagonized by GABAA antagonist. Conclusion Etomidate can protect the cortex and hippocampus against A/R injury to some extent by acting on GABAA recoptor and decreasing intracellular Ca2+ overloading.
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AIM To study the effect of desipramine (DMI ) on proliferation inhibition and apoptosis induction of rat glioma C6 cells. METH ODS Cell proliferation was measured by MTT col- orimetric assay and cells undergoing apoptosis were determined by electron microscope and flow cytometry. The expression of hcf-2 was evaluated by immunohistochemistry. RESULTS DMI could result in the concentration- dependent inhibition of C6 cell proliferation and lead to arrest in GO - G1 phase of cell cycle. The value of Ica and 95% confidence limits were 20.7(17 .3~24 .2) ?mol?L~ 1. DMI(40 ?mol? L-l )-induced apoptosis showed classical apoptotic morphology and the hypodiploid peak appeared on the histogram of FCM in a concentration- dependent man ner, which could be abrogated by cycloheximide(1. 8 ?mol? L- １ ). Meanwhile, DMI (10 ?mol? L- 1 ) could down-regulate the expression of apoptosis associated gene hcl-2. CONCLUSION DMI could inhibit cell proliferation in a concentration dependent manner and induce typical apoptosis of C6 cells.
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Lysine-germanium ( Ge401 ) was a newly synthesized organoger-manium compound in China. The LD50 of Ge401 for mice was 9.26 and 5.62 g/kg po and ip administrations. The inhibition rates of subcutaneously transplanted S-180 sarcoma in mice were 25%, 32% and 55% respectively when ip, po and iv administrations of Ge401 were used. The antitumor activity of cyclophosphamide (30 mg/kg? 2d-1, ip ) in S-180 bearing mice was significantly potentiated by Ge401 (30 mg/kg?d-1, iv ) .
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Alzheimers disease is a progressive neurodegeneration disorder that is characterised by the accumulation of ? amyloid deposits and neurofibrillary tangles. It has been long assumed that the disrupted interneuronal communication that occurs in AD brain does not involve widespread changes in postsynaptic receptor function. However, recent evidence suggests that both the neurotransmitter receptor/G protein modulated adenyl cyclase and the phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruption in AD may provide a reason for the relative lack of success of neurotransmitter replacement therapies for the disorder. Moreover it can direct drug research and development for AD treatment.