Safety profile of 0.0015%tafluprost eye drops in China:a post-marketing observational study

AIM:To investigate the treatment pattern and safety of tafluprost for glaucoma and ocular hypertension(OH)in clinical practice in China.METHODS:This post-marketing observational study included patients who received tafluprost to lower intraocular pressure(IOP)within 30d between September 2017 and March 2020 in 20 hospitals in China.Adverse drug reactions(ADRs)during tafluprost treatment and within 30d after the treatment were collected.RESULTS:A total of 2544 patients were included in this study,of them 58.5%(1488/2544)had primary open angle glaucoma(POAG),21.9%(556/2544)had OH and 19.7%(500/2544)used tafluprost for other reasons.Of 359 ADRs occurred in 10.1%(258/2544)patients,and no serious adverse event occurred.The most common ADR was conjunctival hyperemia(128 ADRs in 124 patients,4.9%).Totally 1670 participants(65.6%)combined tafluprost with carbonic anhydrase inhibitors(CAIs;37.1%,620/1670),sympathomimetics(33.5%,559/1670),β-blockers(33.2%,555/1670),other prostaglandin analogs(PGAs;15.6%,260/1670)and other eye drops(15.1%,253/1670).The highest incidence of conjunctival hyperemia was noted in patients who received tafluprost in combination with other PGAs(23 ADRs in 23 patients,8.8%,23/260)and the lowest was in combination with CAIs(16 ADRs in 16 patients,2.6%,16/620).Tafluprost was applied in primary angle-closure glaucoma(41.6%,208/500),after glaucoma surgery(17.8%,89/500)and after non-glaucoma surgery(15.8%,79/500).CONCLUSION:Tafluprost is safe for POAG and OH,and tolerable when combined with other eye drops and under various clinical circumstances.

Association between depressive mood and body image and menopausal symptoms and sexual function in perimenopausal women

BACKGROUND Perimenopausal is the period when women's ovarian function begins to decline before and after menopause.During this period,women experience a series of mental state changes,such as decreased hormone levels,decreased libido,and even female sexual dysfunction(FSD)in severe cases,which reduces their quality of life.Factors affecting the occurrence of FSD include physiological and nonphysiological factors,among which physiological factors are uncontrollable.Therefore,it is particularly important to ascertain the related non-physiological factors that affect the occurrence of FSD for improving the quality of sexual life of perimenopausal women.AIM To investigate the mediating effect of depressive mood and body image on menopausal symptoms and sexual function in perimenopausal women.METHODS A total of 186 perimenopausal women were enrolled between January 2019 and January 2021 and divided into the FSD(134 cases)and control(52 cases)groups based on the presence and absence of FSD.Clinical data were compared between the two groups.FSD-related factors were analyzed using logistic regression analysis.Hamilton Depression Scale(HAMD),Body Image Scale(BIS),and Menopause Rating Scale(MRS)scores were compared among women with different FSD scores.The correlation of the MRS score with the BIS and HAMD scores and the mediating effect of the BIS and HAMD scores on the MRS score and female sexual function index(FSFI)were analyzed.RESULTS The HAMD and BIS scores were higher in the FSD group than in the control group,and the difference in monthly income between the two groups was statistically significant(all P<0.05).Monthly income of<2000 yuan[odds ratio(OR)=26.586,P=0.000],BIS score(OR=1.590,P=0.000),and HAMD score(OR=1.884,P=0.000)were independent risk factors for FSD.MRS scores were positively correlated with BIS and HAMD scores(r=0.358 and 0.244,P=0.000 and 0.001,respectively)and negatively correlated with FSFI scores(r=-0.433,P=0.000).Body image and depressive mood had partial mediating effects,accounting for 39.90%of the total effect.CONCLUSION Depression and body image play mediating roles between menopausal symptoms and sexual function in perimenopausal women.

Structural and functional damage to the hippocampal neurovascular unit in diabetes-related depression

Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.

Hippocampal insulin resistance and the Sirtuin 1 signaling pathway in diabetes-induced cognitive dysfunction

In the peripheral nervous system,the activation of Sirtuin 1 can improve insulin resistance;however,the role played by Sirtuin 1 in the central nervous system remains unknown.In this study,rat models of diabetes mellitus were generated by a single injection of streptozotocin.At 8 weeks after streptozotocin injection,the Morris water maze test and western blot assays confirmed that the diabetic model rats had learning and memory deficits,insulin resistance,and Sirtuin 1 expression could be detected in the hippocampus.Insulin and the insulin receptor inhibitor S961 were intranasally administered to investigate the regulatory effects of insulin signaling on Sirtuin 1.The results showed that insulin administration improved the impaired cognitive function of diabetic model rats and increased the expression levels of phosphorylated insulin receptor,phosphorylated insulin receptor substrate 1,and Sirtuin 1 in the hippocampus.Conversely,S961 administration resulted in more severe cognitive dysfunction and reduced the expression levels of phosphorylated insulin receptor,phosphorylated insulin receptor substrate 1,and Sirtuin 1.The Sirtuin 1 activator SRT2104 and the inhibitor Sirtinol were injected into the lateral ventricle,which revealed that the activation of Sirtuin 1 increased the expression levels of target of rapamycin complex 1,phosphorylated cAMP-response elementbinding protein,and brain-derived neurotrophic factor.Hippocampal dendritic length and spine density also increased in response to Sirtuin 1 activation.In contrast,Sirtinol decreased the expression levels of target of rapamycin complex 1,phosphorylated cAMP-response elementbinding protein,and brain-derived neurotrophic factor and damaged the dendritic structure.These findings suggest that the Sirtuin 1 signaling pathway plays an important role in the development of insulin resistance-related cognitive deficits in diabetic rats.This study was approved by the Animal Ethics Welfare Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine(approval No.ZYFY201811207)in November 2018.

Abnormal Glu/mGluR2/3/PI3K pathway in the hippocampal neurovascular unit leads to diabetesrelated depression

Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression,and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetesrelated depression.However,the underlying mechanism remains unclear.We hypothesized that diabetes-related depression might be associated with the glutamate(Glu)/metabotropic glutamate receptor2/3(mGluR2/3)/phosphoinositide 3-kinase(PI3K)pathway,activated by glucocorticoid receptors in the hippocampal neurovascular unit.To test this hypothesis,rat hippocampal neurovascular unit models,containing hippocampal neurons,astrocytes,and brain microvascular endothelial cells,were treated with 150 mM glucose and 200μM corticosterone,to induce diabetes-related depression.Our results showed that under conditions of diabetes complicated by depression,hippocampal neurovascular units were damaged,leading to decreased barrier function;elevated Glu levels;upregulated glucocorticoid receptor,vesicular glutamate transporter 3(VGLUT-3),and metabotropic glutamate receptor 2/3(mGluR2/3)expression;downregulated excitatory amino acid transporter 1(EAAT-1)expression;and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase(ERK)/glial cell-derived neurotrophic factor(GDNF)/PI3K signaling pathway.Moreover,the viability of neurons was dramatically reduced in the model of diabetes-related depression,and neuronal apoptosis,and caspase-3 and caspase-9 expression levels,were increased.Our results suggest that the Glu/mGluR2/3/PI3K pathway,induced by glucocorticoid receptor activation in the hippocampal neurovascular unit,may be associated with diabetes-related depression.This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine,China(approval No.HN-ZYFY-2019-11-12)on November 12,2019.

Application of pulse index continuous cardiac output system in elderly patients with acute myocardial infarction complicated by cardiogenic shock: A prospective randomized study

BACKGROUND Cardiogenic shock (CS) secondary to acute myocardial infarction (AMI) complicates management of the condition, and often leads to poor prognosis. Prompt and accurate monitoring of cardiovascular and accompanying hemodynamic changes is crucial in achieving adequate management of the condition. Advances in technology has availed procedures such as pulse index continuous cardiac output (PiCCO), which can offer precise monitoring of cardiovascular functions and hemodynamic parameters. In this study, PiCCO is evaluated for its potential utility in improving management and clinical outcomes among elderly patients with AMI complicated by CS. AIM To assess whether use of the PiCCO system can improve clinical outcomes in elderly patients with AMI complicated by CS.METHODS Patients from emergency intensive care units (EICU) or coronary care units (CCU) were randomized to receive PiCCO monitoring or not. The APACHE II score, SOFA score, hs-TnI, NT-proBNP, PaO2/FiO2 ratio and lactate levels on day 1, 3 and 7 after treatment were compared. The infusion and urine volume at 0-24 h, 24-48 h and 48-72 h were recorded, as were the cardiac index (CI), extravascular lung water index (EVLWI), intrathoracic blood volume index (ITBVI) and global end diastolic volume index (GEDVI) at similar time intervals. RESULTS Sixty patients with AMI complicated by CS were included in the study. The PiCCO group had a significantly lower APACHE II score, SOFA score, hs-TnI and NT-proBNP levels on day 1, 3 and 7 after treatment. The infusion and urine volume during 0-24 h in the PiCCO group were significantly greater, and this group also showed significantly higher ADL scores. Furthermore, the PiCCO group spent lesser days on vasoactive agents, mechanical ventilation, and had a reduced length of stay in EICU/CCU. Additionally, the CI was significantly higher at 48 h and 72 h in the PiCCO group compared with that at 24 h, and the EVLWI, ITBVI and GEDVI were significantly decreased at 48 h and 72 h. CONCLUSION Applying the PiCCO system could improve the clinical outcomes of elderly patients with AMI complicated by CS.

Management strategies in malignant glaucoma secondary to antiglaucoma surgery

AIM：To assess the outcomes of various interventions for malignant glaucoma（MG）.·M ETHODS：A retrospective,comparative analysis of case series were performed on 38 eyes of 35 MG patients treated in Aier Eye Hospital of Wuhan between Jan.2009and Dec.2012.Numerous treatments were administered including medical therapy,neodymium：yttriumaluminium-garnet（Nd：YAG）laser posterior capsulotomy and hyaloidotomy as well as 3 surgical options.The characteristic,treatment option and outcome of MG in every individual patient were reviewed and analyzed among all patients who were followed up for an average of 27.1±9.1mo.·RESULTS：Four eyes of 3 patients achieved complete resolution with medical therapy.Nd：YAG laser posterior capsulotomy and hyaloidotomy were performed on 2 eyes,both of which achieved resolution after initial intervention.Thirty-two eyes were given surgical treatments with anterior vitrectomy-reformation of anterior chamber in13 eyes,phacoemulsification-intraocular lens implantation in 10 eyes and phacoemulsification-intraocular lens implantation-anterior vitrectomy in 9 eyes.Resolution of MG was seen in almost all patients.The mean intraocular pressure decreased from 41.87±9.44 mm Hg at presentation to 15.84±3.73 mm Hg at the last visit.The mean anterior chamber depth improved from 0.28±0.27 mm to 2.28±0.19 mm.Twenty eyes with preoperative visual acuity better than counting figure/50 cm had various visual improvements.Complications occurred in 3 eyes of 3 patients including bleeding at the entry site of vitrectomy into vitreous cavity,corneal endothelial decompensation and allergic to atropine respectively.·CONCLUSION：MG occurs as a result of multiple mechanisms involved simultaneously or sequentially.Medical therapy is advocated as the initial treatment,laser therapy is beneficial in pseudophakic eyes,and different surgical regimen is recommended based on different pathogenesis of MG when non-response occurs to nonsurgical management.MG can be managed successfully by appropriate and timely interventions with good visual outcome.

Effect of Naojian Tablet on cerebral ischemic injury and its prevention mechanism

OBJECTIVE To investigate the prevention and its mechanism of Naojian Tablet,the adjusted prescription from Buyang Huanwu Decoction,during focal ischemic brain injury condition,and study on the main bioactive substance for this function.METHODS To apply the modified middle cerebral artery occlusion(MCAO)model in rats,immunohistochemistry,RT-PCR and Western blotting were applied to determine the expression of CDK5,CDK4/cyclinD1 in the hippocampus tissues in MCAO rat by treating with Naojian Tablet.On the other hand,the processes of metabolism and disposition of several active components in Naojian Tablet and Buyang Huanwu Decoction were analyzed and characterized by using HPLC-Q-TOF method.RESULTS Naojian Tablet(ig,2.41g·kg-1)could significantly decrease the levels of CDK5,CDK4/cyclinD1 in hippocampus tissues in MACO rat after treated by 3d,7d,14 d,28d(P<0.05).The similar mechanism was observed in the Buyang Huanwu Decoction treated MACO rat.Calycosin,fermononetin,senkyunolide and ligustilide in Naojian Tablet was determined simultaneously as the main active ingredient of Naojian Tablet.CONCLUSION The above-mentioned in vivo studies suggested that Naojian Tablet maybe play its prevention effect on nerve cells via its acting on CDK5 signaling and cell cycle pathway,which verified the multi-target and multi active pathways efficiency of tradition Chinese medicine in treating diverse disease.

输出电压对聚焦超声经颅开放血脑屏障有效性及安全性的影响

目的采用现有聚焦超声(FUS)治疗系统,固定基础频率等其他参数,探索输出电压对FUS经颅开放血脑屏障(BBB)有效性及安全性的影响,筛选出合适的输出电压幅值。方法将SPF级雄性昆明小鼠(8~9周龄)随机分为0 mV组、100 mV组、200 mV组、500 mV组和1200 mV组,尾静脉注射微泡后给予FUS辐照(Bregma-2.7 mm,lateral+2.5 mm),再经尾静脉注入伊文思蓝(EB),4 h后取材,用脑组织的EB含量表征FUS经颅开放BBB的有效性指标,用HE染色探查安全性。结果0 mV组小鼠BBB未开放。各组小鼠脑组织EB含量比较,差异有统计学意义(P<0.05),且随着输出电压升高,脑组织EB含量显著升高(P<0.05)。0 mV组和100mV、200 mV组小鼠大脑受超声辐照区域脑组织正常,均无红细胞渗出;500 mV组、1200 mV组小鼠大脑超声作用区域脑组织有不同程度红细胞渗出。结论当FUS基础频率为1 MHz,脉宽10 ms,总辐照时间120 s,脉冲重复频率为1 Hz,SonoVue~?六氟化硫微泡剂量2.5μL/g的情况下,输出电压为200 mV可经颅、高效、安全地开放BBB,是较为合适的输出电压幅值。

Inhibitory effect of compound NS5806 on cardiac transient outward potassium channel dependents on interaction between auxiliary subunits

OBJECTIVE Transient outward potassium current(I_(to)) plays a crucial role in cardiac phase 1 repolarization and the channels are assembled by pore-forming α-subunits(K_v4.2 or K_v4.3) and auxiliary subunits(KCh IP2 and DPP6).Previous studies have found that the compound NS5806 increases I_(to) in canine ventricular cardiomyocytes through slowing current decay.Here,we reported that NS5806 produced an acute inhibitory action on I_(to) in mouse ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes(hi PS-CM).METHODS Whole-cell patch-clamp was used to record I_(to) in native myocytes and in HEK cells expressing cloned K_v4.x/KCh IP2/DPP6 channels;Western-blot detected the channel protein expression.RESULTS In isolated mouse ventricular cardiomyocytes,NS5806(0.1-30 μmol·L^(-1)) inhibited I_(to) in a concentration-dependent manner with IC50 of 6.6±1.9 μmol·L^(-1).The current decay was significantly accelerated with a time constant from 53.8±5.5 to 41.8±3.0 ms at +60 m V(P<0.01).Similarly,NS5806 concentration-dependently reduced the I_(to) peak current amplitude with an acceleration of current decay.In addition,NS5806 increased I Kv4.2/KCh IP2 and delayed current decay,but decreased I Kv4.2/KCh IP2/DPP6 with the acceleration of current decay.The inhibitory action on the current was more potent if DPP6 expression level was increased from K_v4.2/KCh IP2/DPP6 1∶1∶1 to 1∶1∶3.Western-blot showed a higher expression of DPP6 protein in mouse heart and in hi PS-CM compared to canine heart.Moreover,specific knock-down DPP6 expression by si RNA antagonized the inhibitory action of NS5806 in hi PS-CM.Our results pointed to an important role of DPP6 subunit in the regulation of NS5806 on the channel.By using molecular docking simulation,five interaction sites with high possibility between KCh IP2 and DPP6 were identified.Mutations of those sites changed the inhibitory action of NS58056 into excitatory effect on the current with the delay of current decay.CONCLUSION NS5806 significantly inhibits I_(to) by accelerating current decay in mouse cardiomyocytes and hi PS-CM.The effect depends on the interaction between DPP6 and KCh IP2 subunits.

Network Pharmacology-Based and Pharmacological Evaluation of the Effects of Curcumae Radixon Cerebral Ischemia-Reperfusion Injury

Objective: This study aimed to investigate the network pharmacology of curcumae radix(CR, Yujin) and explore the mechanism of CR in the treatment of cerebral ischemia-reperfusion injury(CIRI). Materials and Methods: Network analysis and pharmacological evaluation were performed to explore the protective role of CR to treat CIRI. The potential target genes of the active components and CIRI were identified using SwissTarget Prediction, Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine, GeneCards, and Online Mendelian Inheritance in Man. Furthermore, network analysis was performed using Cytoscape software.Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the R software. In vivo experiments were performed using the water extract of CR(WECR) on PC12 cells induced by hypoxia/reoxygenation(H/R) to simulate ischemia/reperfusion injury. Results: The results exhibited that 21 active compounds identified in CR were associated with 73 targets of CIRI. Functional analysis showed that multiple pathways, including response to stress, regulation of apoptotic process, and hypoxia-inducible factor 1 signaling pathway, were significantly enriched. In addition, STAT3, IL4, HIFIA, and CTNNB1 were predicted to be the most important genes among the 36 hub genes. Furthermore, WECR treatment significantly improved PC12 cell injury and decreased apoptosis levels in cells induced by H/R, with malondialdehyde contents reduced and superoxide dismutase or glutathione peroxidase levels increased. Conclusions: Network analysis and pharmacological evaluation of CR could provide valuable directions for further research on CR and improve comprehension of CIRI.

Advances in electrochemical reduction of carbon dioxide to formate over bismuth-based catalysts

Selective CO_(2) reduction to formate with highadded value is one of the most technologically and economically feasible pathways to realize electrochemical CO_(2) fixation. Bismuth-based catalysts have the advantages of nontoxicity, low cost, high abundance, as well as excellent stability. In addition, bismuth-based catalysts display excellent selectivity for the electrochemical reduction of CO_(2) to formate in aqueous electrolytes due to high-hydrogen evolution overpotential. Hence, bismuthbased catalysts are by far the most commercially available materials for electrochemical reduction of CO_(2) to formate.In this review, the electrochemical reduction of CO_(2) to formate over bismuth-based catalysts is elaborated. Firstly,this review describes performance evaluation indexes,evaluation systems and reaction mechanisms of the electrochemical reduction of CO_(2) to formate over bismuthbased catalysts. Subsequently, the research means to reveal the reaction mechanism of electrochemical reduction of CO_(2) to formate over bismuth-based catalysts and the performance improvement strategies of the reaction are described in detail. Finally, the opportunities and challenges in this encouraging field are discussed. We believe that this review will contribute to further development of electrochemical reduction of CO_(2) to formate over bismuthbased catalysts.