Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type Ⅲ domain-containing protein 5(FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective f...Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type Ⅲ domain-containing protein 5(FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.展开更多
Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a ...Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.展开更多
The phase structure and electrochemical properties of La1.7+xMg1.3-x(NiCoMn)9.3(x=0-0.4) alloys were investigated. The XRD analysis reveals that the alloys consist of LaNi5 phase and other phases, such as LaMg2Ni...The phase structure and electrochemical properties of La1.7+xMg1.3-x(NiCoMn)9.3(x=0-0.4) alloys were investigated. The XRD analysis reveals that the alloys consist of LaNi5 phase and other phases, such as LaMg2Ni9 phase (PuNi3 structure) and La4MgNi19 phases (Ce5Co19+Pr5Co19 structure, namely A5B19 type). With the increase of the x value, the LaMg2Ni9 phase fades away and La4MgNi19 phases appear, while the abundance of LaNi5 phase firstly increases and then decreases. At the same time, the cell volume of LaNi5 phase and LaMg2Ni9 phase decreases. The electrochemical measurement shows that alloy electrodes could be activated in 4-5 cycles, and with the increase of the x value, the maximum discharge capacity gradually increases from 330.9 mA-h/g (x=0) to 366.8 mA-h/g (x=0.4), but the high-rate dischargeability (HRD) and cyclic stability (S) decrease somewhat (x=0.4, HRD600=82.32%, S100=73.8%). It is found that the HRD is mainly controlled by the electrocatalytic activity on the alloy electrode surface, and the decline of cyclic stability is due to the appearance of A5B19 type phase with larger hydrogen storage capacity, which leads to larger volume expansion and more intercrystalline stress and then easier pulverization during charging/discharging.展开更多
Aim: To assess the efficacy and safety of tadalafil in comparison to a placebo, when taken on demand for 12 weeks by East/Southeast Asian men with erectile dysfunction (ED), Methods: This multicenter, randomized, ...Aim: To assess the efficacy and safety of tadalafil in comparison to a placebo, when taken on demand for 12 weeks by East/Southeast Asian men with erectile dysfunction (ED), Methods: This multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted at 17 centers across East and Southeast Asia between August 2002 and February 2003. Men more than 18 years of age with mild to severe ED of various etiologies were randomized to receive a placebo or 20 mg of tadalafil taken as needed (maximum once daily). Efficacy assessments included the International Index of Erectile Function, the Sexual Encounter Profile diary and Global Assessment Questions. Results: Tadalafil significantly improved erectile function as compared to the placebo (P 〈 0.001). At the endpoint, the patients receiving 20 mg of tadalafil reported a greater mean per patient percentage of successful intercourse attempts (Sexual Encounter Profile question 3: 70.9% compared to 33.5% in the placebo) and a greater proportion of improved erections (Global Assessment Question: 86.2% compared to 30.1%). Most (≥3%) treatment emergent adverse events were mild or moderate. The most common treatment emergent adverse events were headache, back pain, dizziness and dyspepsia. Conclusion: Tadalafil was an effective and well-tolerated treatment for ED in East and Southeast Asian men.展开更多
Erectile response is centrally and peripherally regulated by androgens. The original insights into the mechanisms of action of androgens were that androgens particularly exert effects on libido and that erections in r...Erectile response is centrally and peripherally regulated by androgens. The original insights into the mechanisms of action of androgens were that androgens particularly exert effects on libido and that erections in response to erotic stimuli were relatively androgen-independent. It was shown that sexual functions in men required androgen levels at the low end of reference values of testosterone. So it seemed that testosterone was not useful treatment for men with erectile difficulties, particularly following the advent of the phosphodiesterase type 5 (PDE5) inhibitors. However, approximately 50% of those treated with PDE5 inhibitors discontinue their treatment. A number of recent developments shed new light on testosterone treatment of erectile dysfunction (ED) in aging men. (1) A recent insight is that, in contrast to younger men, elderly men might require higher levels of testosterone for normal sexual functioning. (2) Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men, and that testosterone improves the therapeutical response to PDE5 inhibitors considerably. (3) There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, reversible upon androgen replacement. The synthesis of PDE5 is upregulated by androgens, and the arterial inflow into the penis is improved by giving androgen. The above invites a re-examination of the merits of giving testosterone to aging men with ED. The beneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment. (Asian J Androl 2006 Jan; 8: 3-9)展开更多
Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion.Downregulation of microRNA(miR)-455-5p after ischemic stroke has been consider...Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion.Downregulation of microRNA(miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia.However,the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated.In this study,mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion.Agomir-455-5p,antagomir-455-5p,and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion(MCAO).The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood.Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue,reduced the cerebral infarct volume,and improved neurological function.Furthermore,primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion.miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels,inhibited microglia activation,and reduced the production of the inflammatory factors tumor necrosis factor-αand interleukin-1β.These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.展开更多
Summary: To further investigate the mechanisms of action of icariin (ICA), we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit...Summary: To further investigate the mechanisms of action of icariin (ICA), we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of ^125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil (Sild). Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type Ⅴ (PDE5) in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that ICA increased cGMP concentrations directly (P〈0.05), but there was no significant effect on cAMP concentrations (P〉0.05). In the presence of sodium nitroprusside (SNP), a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose (P〈0.01). Their EC50 was 4.62 (ICA) and 0.42 (Sild) μmol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly (P〉0.05). There were PDE5A 1 and PDE5A2 mRNA expressions in rat cor- pus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly (P〈 0.01). The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.展开更多
The Erectile Dysfunction Observational Study (EDOS) is a 6-months observational prospective multicentric study enrolling men with erectile dysfunction (ED) who asked, to be started on a treatment or to change a pr...The Erectile Dysfunction Observational Study (EDOS) is a 6-months observational prospective multicentric study enrolling men with erectile dysfunction (ED) who asked, to be started on a treatment or to change a previous treatment. Aims of the study were to analyse the pattern of treatment and compare the efficacy of treatments used. Patients were enrolled during a normal hospital visit and were prescribed a treatment for ED. They were asked at baseline and after 3 and 6 months, to answer a set of questions from the International Index of Erectile Function, Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and Short Form of the Psychological and Interpersonal Relationships Scale questionnaires (SF-PAIRS). Clinicians were free to prescribe any therapy for ED available in the market, and to change therapy at any time during the study. Out of 1 338 patients, available for analysis at 6 months, 624 (47%) changed their treatment during the study and 714 (53%) continued with the drug prescribed at baseline. Patients assuming tadalafil had a significantly higher probability of maintaining the same treatment compared to sildenafil or vardenafil. There was no clinically significant difference in terms of efficacy, patient satisfaction, self-confidence and spontaneity between the different inhibitors of PDE5. The ‘time concerns' domain score of SF-PAIRS, was statistically better in patients assuming tadalafil. In conclusion sildenafil, vardenafil and tadalafil show similar efficacy in the clinical practice. However, patients receiving tadalafil display a lower risk to discontinue or change the treatment.展开更多
Aim: To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 (PDE5) inhibitor, on penile erection in obese rats. Meth...Aim: To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 (PDE5) inhibitor, on penile erection in obese rats. Methods: The rats were fed a high-energy diet for 12 weeks and divided into three groups: an obesity-resistant (OR) control group, an obesity-prone (OP) control group, and an OP-DA-8159 treatment (DA-8159) group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. Results: In the OP control group, the maximum intracavernous pressure (ICP) and ICP/blood pressure (ICP/BP) ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve (AUC) of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. Conclusion: These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction (ED) can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.展开更多
The effects of low-Co AB_5 type hydrogen storage alloys prepared by quenchingand annealing on the performances of MH-Ni batteries were investigated, and the characteristics ofthe low-Co AB_5 type hydrogen storage allo...The effects of low-Co AB_5 type hydrogen storage alloys prepared by quenchingand annealing on the performances of MH-Ni batteries were investigated, and the characteristics ofthe low-Co AB_5 type hydrogen storage alloys were compared with those of the high-Co AB_5 typehydrogen storage alloy as well. The results showed that the faster the cooling of the low-Cohydrogen storage alloy is, the better homogeneity of the chemical composition for the alloy and thelonger cycle life of the battery are, but the electrochemical discharge capacity and high-ratedischarge ability are reduced. The high-rate discharge ability and charge retention of MH-Nibatteries for the conventional as-cast annealed low-Co hydrogen storage alloy were superior to thosefor the rapidly quenched low-Co hydrogen storage alloy and the high-Co hydrogen storage alloy, buta little inferior in the cycle life.展开更多
Erectile dysfunction(ED) is a common condition among male chronic kidney disease(CKD) patients.Its prevalence is estimated to be approximately 80% among these patients.It has been well established that the production ...Erectile dysfunction(ED) is a common condition among male chronic kidney disease(CKD) patients.Its prevalence is estimated to be approximately 80% among these patients.It has been well established that the production of nitric oxide from the cavernous nerve and vascular endothelium and the subsequent production of cyclic GMP are critically important in initiating and maintaining erection.Factors affecting these pathways can induce ED.The etiology of ED in CKD patients is multifactorial.Factors including abnormalities in gonadal-pituitary system,disturbance in autonomic nervous system,endothelial dysfunction,anemia(and erythropoietin deficiency),secondary hyperparathyroidism,drugs,zinc deficiency,and psychological problems are implicated in the occurrence of ED.An improvement of general conditions is the first step of treatment.Sufficient dialysis and adequate nutritional intake are necessary.In addition,control of anemia and secondary hyperparathyroidism is required.Changes of drugs that potentially affect erectile function may be necessary.Further,zinc supplementation may be necessary whenzinc deficiency is suspected.Phosphodiesterase type 5 inhibitors(PDE5Is) are commonly used for treating ED in CKD patients,and their efficacy was confirmed by many studies.Testosterone replacement therapy in addition to PDE5 Is may be useful,particularly for CKD patients with hypogonadism.Renal transplantation may restore erectile function.ED is an early marker of cardiovascular disease(CVD),which it frequently precedes; therefore,it is crucial to examine the presence of ED in CKD patients not only for the improvement of the quality of life but also for the prevention of CVD attack.展开更多
The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might req...The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.展开更多
Irritable bowel syndrome(IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patient...Irritable bowel syndrome(IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patients suffer from the constipation subtype of IBS(IBS-C), most commonly afflicting older individuals and those with a lower socioeconomic status. Conventional pharmacologic and nonpharmacologic treatment options have limited efficacies and/or significant adverse events, which lead to increased long-term health care expenditures. Failure to effectively treat IBS-C patients over the past decades has largely been due to a poor understanding of disease pathophysiology, lack of a global view of the patient, and an inappropriate selection of patients and treatment endpoints in clinical trials. In recent years, however, more effective and safer drugs have been developed for the treatment of IBS-C. The advancement in the area of pharmacologic treatment is based on new knowledge of the pathophysiologic basis of IBS-C and the development of drugs with increased selectivity within pharmacologic classes with recognized efficacies. This narrative review covers the spectrum of available drugs and their mechanisms of action, as well as the efficacy and safety profiles of each as determined in relevant clinical trials that have investigated treatment options for IBS-C and chronic constipation. A brief summary of laxative-based treatment options is presented, followed by up-to-date assessments for three classes of drugs: prokinetics, prosecretory agents, and bile acid modulators.展开更多
Many aging men will experience lower urinary tract symptoms(LUTS).Phosphodiesterase type 5(PDE5)inhibitors have shown promise in treating LUTS in these patients.PDE5 inhibitors mediate their effects through several pa...Many aging men will experience lower urinary tract symptoms(LUTS).Phosphodiesterase type 5(PDE5)inhibitors have shown promise in treating LUTS in these patients.PDE5 inhibitors mediate their effects through several pathways including cAMP,NO/cGMP,Kchannel modulated pathways,and the L-cysteine/H2S pathway.PDE5 inhibitors exert their effect in muscle cells,nerve fibers,and interstitial cells(ICs).The use of PDE5 inhibitors led to improvement in LUTS.This included urodynamic parameters.PDE5 inhibitors may play a significant role in LUTS due to their effect on the bladder rather than the prostate.展开更多
AIM: To review the efficacy of phosphodiesterase type 5 inhibitors(PDE5-Is) in lower urinary tract symptoms(LUTS) suggestive of benign prostate hyperplasia(LUTS/BPH). METHODS: A comprehensive research was conducted to...AIM: To review the efficacy of phosphodiesterase type 5 inhibitors(PDE5-Is) in lower urinary tract symptoms(LUTS) suggestive of benign prostate hyperplasia(LUTS/BPH). METHODS: A comprehensive research was conducted to identify all publications relating to benign prostate hyperplasia and treatment with sildenafil, vardenafil and tadalafil. To assess the efficacy, the changes in total international prostate symptom score(IPSS), IPSS subscore including voiding, storage and quality of life(Qo L), Benign prostatic hyperplasia Impact Index(BII), maximum urinary flow rate(Qmax) and the International Index of Erectile Function(IIEF) were extracted. A meta-analytical technique was used for the analysis of integrated data from the included studies to evaluate the mean difference in the results. RESULTS: Total IPSS score, IIEF and BII showed a significant improvement in trials in which LUTS/BPH with or without erectile dysfunction(ED) were compared with the placebo. For LUTS/BPH, the mean differences of total IPSS score, IIEF and BII are-2.17, 4.88 and-0.43, P < 0.00001, respectively. For LUTS/BPH with comorbid ED, the mean difference are-1.97, 4.54 and-0.52, P < 0.00001, respectively. PDE5-Is appear to improve IPSS storage, voiding and Qo L subscore(mean difference =-0.71,-1.23 and-0.33, P < 0.00001, respectively). Although four doses of tadalafil(2.5, 5, 10 and 20 mg) failed to reach significance in Qmax(mean difference = 0.22, P = 0.10), the 5 mg dose of tadalafil significantly improved the Qmax(mean difference = 0.33, P = 0.03).CONCLUSION: PED5-Is demonstrated efficacy for improving LUTS in BPH patients with or without ED and could be considered to be the first line treatment for LUTS/BPH.展开更多
LPCNi 3.55 Co 0.75 Mn 0.4 Al 0.3 hydrogen storage alloy was investigated, and the effects of thickness of its strip casting ingots(as cast) on the electrochemical performances were discussed. It was ...LPCNi 3.55 Co 0.75 Mn 0.4 Al 0.3 hydrogen storage alloy was investigated, and the effects of thickness of its strip casting ingots(as cast) on the electrochemical performances were discussed. It was found that the 0.2 C discharge capacity increased with the increase of the thickness (from 1 mm to 10 mm) of the ingots, mainly due to the enlargement of the unit cell volume; Among the thickness of the ingots in our study, 10 mm sample showed a better activation property; LPCNi 3.55 Co 0.75 Mn 0.4 Al 0.3 alloy with 10mm showed higher comprehensive properties than those with other thickness under 1C rate.展开更多
基金supported by Cure Alzheimer’s Fund (to RET and SHC)JPB Foundation (to RET),and R56AG072054 (to SHC)。
文摘Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type Ⅲ domain-containing protein 5(FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.
基金supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY)the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR)+4 种基金Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ)Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW)the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW)Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW)the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)
文摘Neuroinflammation and the NACHT,LRR,and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI).Maraviroc,a C-C chemokine receptor type 5 antagonist,has been viewed as a new therapeutic strategy for many neuroinflammatory diseases.We studied the effect of maraviroc on TBI-induced neuroinflammation.A moderate-TBI mouse model was subjected to a controlled cortical impact device.Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days.Western blot,immunohistochemistry,and TUNEL(terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI.Our results suggest that maraviroc administration reduced NACHT,LRR,and PYD domains-containing protein 3 inflammasome activation,modulated microglial polarization from M1 to M2,decreased neutrophil and macrophage infiltration,and inhibited the release of inflammatory factors after TBI.Moreover,maraviroc treatment decreased the activation of neurotoxic reactive astrocytes,which,in turn,exacerbated neuronal cell death.Additionally,we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score,rotarod test,Morris water maze test,and lesion volume measurements.In summary,our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI,and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.
基金Project (2008CL068L) supported by the Natural Science Research Project of Higher Education of Jiangsu Province, ChinaProject (50901036) supported by the National Natural Science Foundation of China
文摘The phase structure and electrochemical properties of La1.7+xMg1.3-x(NiCoMn)9.3(x=0-0.4) alloys were investigated. The XRD analysis reveals that the alloys consist of LaNi5 phase and other phases, such as LaMg2Ni9 phase (PuNi3 structure) and La4MgNi19 phases (Ce5Co19+Pr5Co19 structure, namely A5B19 type). With the increase of the x value, the LaMg2Ni9 phase fades away and La4MgNi19 phases appear, while the abundance of LaNi5 phase firstly increases and then decreases. At the same time, the cell volume of LaNi5 phase and LaMg2Ni9 phase decreases. The electrochemical measurement shows that alloy electrodes could be activated in 4-5 cycles, and with the increase of the x value, the maximum discharge capacity gradually increases from 330.9 mA-h/g (x=0) to 366.8 mA-h/g (x=0.4), but the high-rate dischargeability (HRD) and cyclic stability (S) decrease somewhat (x=0.4, HRD600=82.32%, S100=73.8%). It is found that the HRD is mainly controlled by the electrocatalytic activity on the alloy electrode surface, and the decline of cyclic stability is due to the appearance of A5B19 type phase with larger hydrogen storage capacity, which leads to larger volume expansion and more intercrystalline stress and then easier pulverization during charging/discharging.
文摘Aim: To assess the efficacy and safety of tadalafil in comparison to a placebo, when taken on demand for 12 weeks by East/Southeast Asian men with erectile dysfunction (ED), Methods: This multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted at 17 centers across East and Southeast Asia between August 2002 and February 2003. Men more than 18 years of age with mild to severe ED of various etiologies were randomized to receive a placebo or 20 mg of tadalafil taken as needed (maximum once daily). Efficacy assessments included the International Index of Erectile Function, the Sexual Encounter Profile diary and Global Assessment Questions. Results: Tadalafil significantly improved erectile function as compared to the placebo (P 〈 0.001). At the endpoint, the patients receiving 20 mg of tadalafil reported a greater mean per patient percentage of successful intercourse attempts (Sexual Encounter Profile question 3: 70.9% compared to 33.5% in the placebo) and a greater proportion of improved erections (Global Assessment Question: 86.2% compared to 30.1%). Most (≥3%) treatment emergent adverse events were mild or moderate. The most common treatment emergent adverse events were headache, back pain, dizziness and dyspepsia. Conclusion: Tadalafil was an effective and well-tolerated treatment for ED in East and Southeast Asian men.
文摘Erectile response is centrally and peripherally regulated by androgens. The original insights into the mechanisms of action of androgens were that androgens particularly exert effects on libido and that erections in response to erotic stimuli were relatively androgen-independent. It was shown that sexual functions in men required androgen levels at the low end of reference values of testosterone. So it seemed that testosterone was not useful treatment for men with erectile difficulties, particularly following the advent of the phosphodiesterase type 5 (PDE5) inhibitors. However, approximately 50% of those treated with PDE5 inhibitors discontinue their treatment. A number of recent developments shed new light on testosterone treatment of erectile dysfunction (ED) in aging men. (1) A recent insight is that, in contrast to younger men, elderly men might require higher levels of testosterone for normal sexual functioning. (2) Several studies have indicated that PDE5 inhibitors are not always sufficient to restore erectile potency in men, and that testosterone improves the therapeutical response to PDE5 inhibitors considerably. (3) There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological substrate of erectile capacity, reversible upon androgen replacement. The synthesis of PDE5 is upregulated by androgens, and the arterial inflow into the penis is improved by giving androgen. The above invites a re-examination of the merits of giving testosterone to aging men with ED. The beneficial effects of PDE5 inhibitors may only be optimally expressed in a eugonadal environment. (Asian J Androl 2006 Jan; 8: 3-9)
基金supported by the National Natural Science Foundation of China,Nos.82071283(to QH)and 81671130(to QH)Medical Engineering Cross Research Foundation of Shanghai Jiao Tong University of China,No.YG2017MS83(to QH)from Shanghai Municipal Science and Technology Commission Medical Guidance Science and Technology Support Project of China,No.19411968400(to QYM).
文摘Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion.Downregulation of microRNA(miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia.However,the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated.In this study,mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion.Agomir-455-5p,antagomir-455-5p,and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion(MCAO).The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood.Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue,reduced the cerebral infarct volume,and improved neurological function.Furthermore,primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion.miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels,inhibited microglia activation,and reduced the production of the inflammatory factors tumor necrosis factor-αand interleukin-1β.These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response.
文摘Summary: To further investigate the mechanisms of action of icariin (ICA), we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of ^125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil (Sild). Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type Ⅴ (PDE5) in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that ICA increased cGMP concentrations directly (P〈0.05), but there was no significant effect on cAMP concentrations (P〉0.05). In the presence of sodium nitroprusside (SNP), a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose (P〈0.01). Their EC50 was 4.62 (ICA) and 0.42 (Sild) μmol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly (P〉0.05). There were PDE5A 1 and PDE5A2 mRNA expressions in rat cor- pus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly (P〈 0.01). The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.
文摘The Erectile Dysfunction Observational Study (EDOS) is a 6-months observational prospective multicentric study enrolling men with erectile dysfunction (ED) who asked, to be started on a treatment or to change a previous treatment. Aims of the study were to analyse the pattern of treatment and compare the efficacy of treatments used. Patients were enrolled during a normal hospital visit and were prescribed a treatment for ED. They were asked at baseline and after 3 and 6 months, to answer a set of questions from the International Index of Erectile Function, Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and Short Form of the Psychological and Interpersonal Relationships Scale questionnaires (SF-PAIRS). Clinicians were free to prescribe any therapy for ED available in the market, and to change therapy at any time during the study. Out of 1 338 patients, available for analysis at 6 months, 624 (47%) changed their treatment during the study and 714 (53%) continued with the drug prescribed at baseline. Patients assuming tadalafil had a significantly higher probability of maintaining the same treatment compared to sildenafil or vardenafil. There was no clinically significant difference in terms of efficacy, patient satisfaction, self-confidence and spontaneity between the different inhibitors of PDE5. The ‘time concerns' domain score of SF-PAIRS, was statistically better in patients assuming tadalafil. In conclusion sildenafil, vardenafil and tadalafil show similar efficacy in the clinical practice. However, patients receiving tadalafil display a lower risk to discontinue or change the treatment.
文摘Aim: To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 (PDE5) inhibitor, on penile erection in obese rats. Methods: The rats were fed a high-energy diet for 12 weeks and divided into three groups: an obesity-resistant (OR) control group, an obesity-prone (OP) control group, and an OP-DA-8159 treatment (DA-8159) group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured. Results: In the OP control group, the maximum intracavernous pressure (ICP) and ICP/blood pressure (ICP/BP) ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve (AUC) of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159. Conclusion: These results demon- strate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction (ED) can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.
文摘The effects of low-Co AB_5 type hydrogen storage alloys prepared by quenchingand annealing on the performances of MH-Ni batteries were investigated, and the characteristics ofthe low-Co AB_5 type hydrogen storage alloys were compared with those of the high-Co AB_5 typehydrogen storage alloy as well. The results showed that the faster the cooling of the low-Cohydrogen storage alloy is, the better homogeneity of the chemical composition for the alloy and thelonger cycle life of the battery are, but the electrochemical discharge capacity and high-ratedischarge ability are reduced. The high-rate discharge ability and charge retention of MH-Nibatteries for the conventional as-cast annealed low-Co hydrogen storage alloy were superior to thosefor the rapidly quenched low-Co hydrogen storage alloy and the high-Co hydrogen storage alloy, buta little inferior in the cycle life.
文摘Erectile dysfunction(ED) is a common condition among male chronic kidney disease(CKD) patients.Its prevalence is estimated to be approximately 80% among these patients.It has been well established that the production of nitric oxide from the cavernous nerve and vascular endothelium and the subsequent production of cyclic GMP are critically important in initiating and maintaining erection.Factors affecting these pathways can induce ED.The etiology of ED in CKD patients is multifactorial.Factors including abnormalities in gonadal-pituitary system,disturbance in autonomic nervous system,endothelial dysfunction,anemia(and erythropoietin deficiency),secondary hyperparathyroidism,drugs,zinc deficiency,and psychological problems are implicated in the occurrence of ED.An improvement of general conditions is the first step of treatment.Sufficient dialysis and adequate nutritional intake are necessary.In addition,control of anemia and secondary hyperparathyroidism is required.Changes of drugs that potentially affect erectile function may be necessary.Further,zinc supplementation may be necessary whenzinc deficiency is suspected.Phosphodiesterase type 5 inhibitors(PDE5Is) are commonly used for treating ED in CKD patients,and their efficacy was confirmed by many studies.Testosterone replacement therapy in addition to PDE5 Is may be useful,particularly for CKD patients with hypogonadism.Renal transplantation may restore erectile function.ED is an early marker of cardiovascular disease(CVD),which it frequently precedes; therefore,it is crucial to examine the presence of ED in CKD patients not only for the improvement of the quality of life but also for the prevention of CVD attack.
文摘The diagnosis and treatment of erectile dysfunction has changed dramatically since the availability of safe and effective oral therapies. Unfortunately, not all men can be adequately treated in this way, and might require more invasive testing to diagnose and treat the specific cause of their dysfunction. This review looks at the tests and strategies available for men who cannot be treated by oral therapy alone.
文摘Irritable bowel syndrome(IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patients suffer from the constipation subtype of IBS(IBS-C), most commonly afflicting older individuals and those with a lower socioeconomic status. Conventional pharmacologic and nonpharmacologic treatment options have limited efficacies and/or significant adverse events, which lead to increased long-term health care expenditures. Failure to effectively treat IBS-C patients over the past decades has largely been due to a poor understanding of disease pathophysiology, lack of a global view of the patient, and an inappropriate selection of patients and treatment endpoints in clinical trials. In recent years, however, more effective and safer drugs have been developed for the treatment of IBS-C. The advancement in the area of pharmacologic treatment is based on new knowledge of the pathophysiologic basis of IBS-C and the development of drugs with increased selectivity within pharmacologic classes with recognized efficacies. This narrative review covers the spectrum of available drugs and their mechanisms of action, as well as the efficacy and safety profiles of each as determined in relevant clinical trials that have investigated treatment options for IBS-C and chronic constipation. A brief summary of laxative-based treatment options is presented, followed by up-to-date assessments for three classes of drugs: prokinetics, prosecretory agents, and bile acid modulators.
文摘Many aging men will experience lower urinary tract symptoms(LUTS).Phosphodiesterase type 5(PDE5)inhibitors have shown promise in treating LUTS in these patients.PDE5 inhibitors mediate their effects through several pathways including cAMP,NO/cGMP,Kchannel modulated pathways,and the L-cysteine/H2S pathway.PDE5 inhibitors exert their effect in muscle cells,nerve fibers,and interstitial cells(ICs).The use of PDE5 inhibitors led to improvement in LUTS.This included urodynamic parameters.PDE5 inhibitors may play a significant role in LUTS due to their effect on the bladder rather than the prostate.
基金Supported by The Korea Health Technology R and D Project through the Korea Health Industry Development Institute(KHIDI)by the Ministry of Health and Welfare,South Korea,No.HI13C0104
文摘AIM: To review the efficacy of phosphodiesterase type 5 inhibitors(PDE5-Is) in lower urinary tract symptoms(LUTS) suggestive of benign prostate hyperplasia(LUTS/BPH). METHODS: A comprehensive research was conducted to identify all publications relating to benign prostate hyperplasia and treatment with sildenafil, vardenafil and tadalafil. To assess the efficacy, the changes in total international prostate symptom score(IPSS), IPSS subscore including voiding, storage and quality of life(Qo L), Benign prostatic hyperplasia Impact Index(BII), maximum urinary flow rate(Qmax) and the International Index of Erectile Function(IIEF) were extracted. A meta-analytical technique was used for the analysis of integrated data from the included studies to evaluate the mean difference in the results. RESULTS: Total IPSS score, IIEF and BII showed a significant improvement in trials in which LUTS/BPH with or without erectile dysfunction(ED) were compared with the placebo. For LUTS/BPH, the mean differences of total IPSS score, IIEF and BII are-2.17, 4.88 and-0.43, P < 0.00001, respectively. For LUTS/BPH with comorbid ED, the mean difference are-1.97, 4.54 and-0.52, P < 0.00001, respectively. PDE5-Is appear to improve IPSS storage, voiding and Qo L subscore(mean difference =-0.71,-1.23 and-0.33, P < 0.00001, respectively). Although four doses of tadalafil(2.5, 5, 10 and 20 mg) failed to reach significance in Qmax(mean difference = 0.22, P = 0.10), the 5 mg dose of tadalafil significantly improved the Qmax(mean difference = 0.33, P = 0.03).CONCLUSION: PED5-Is demonstrated efficacy for improving LUTS in BPH patients with or without ED and could be considered to be the first line treatment for LUTS/BPH.
文摘LPCNi 3.55 Co 0.75 Mn 0.4 Al 0.3 hydrogen storage alloy was investigated, and the effects of thickness of its strip casting ingots(as cast) on the electrochemical performances were discussed. It was found that the 0.2 C discharge capacity increased with the increase of the thickness (from 1 mm to 10 mm) of the ingots, mainly due to the enlargement of the unit cell volume; Among the thickness of the ingots in our study, 10 mm sample showed a better activation property; LPCNi 3.55 Co 0.75 Mn 0.4 Al 0.3 alloy with 10mm showed higher comprehensive properties than those with other thickness under 1C rate.