Exploration of Decision-Making Methods Based on Syndrome Differentiation by “Data-Knowledge” Dual-Driven Models： A Case Study of Gastric Precancerous State / 中医杂志

Data analysis models may assist the transmission of traditional Chinese medicine （TCM） experience and clinical diagnosis and treatment， and the possibility of constructing a “data-knowledge” dual-drive model was explored by taking gastric precancerous state as an example. Data-driven is to make clinical decisions around data analysis， and its syndrome-differentiation decision-making research relies on hidden structural models and partially observable Markov decision-making processes to identify the etiology of diseases， syndrome elements， evolution of pathogenesis， and syndrome differentiation protocols； knowledge-driven is to make use of data and information to promote decision-making and action processes， and its syndrome-differentiation decision-making research relies on convolutional neural networks to improve the accuracy of local disease identification and syndrome differentiation. The “data-knowledge” dual-driven model can make up for the shortcomings of single-drive numerical simulation accuracy， and achieve a balance between local disease identification and macroscopic syndrome differentiation. On the basis of previous research， we explored the construction method of diagnostic assisted decision-making platform for gastric precancerous state， and believed that the diagnostic and decision-making ability of doctors can be extended through the assistance of machines and algorithms. Meanwhile， the related research methods were integrated and the core features of gastric precancerous state based on TCM syndrome differentiation and endoscopic pathology diagnosis and prediction were obtained， and the elements of endoscopic pathology recognition based on TCM syndrome differentiation were explored， so as to provide ideas for the in-depth research and innovative application of cutting-edge data analysis technology in the field of intelligent TCM syndrome differentiation.

An accurate and reliable analytical strategy for simultaneous determination of target furanocoumarins and flavonoids in cosmetic and pharmaceutical samples by ultra-high performance supercritical fluid chromatography.

Furanocoumarins and flavonoids have various important biological activities and wide application. In the present study, a rapid and reliable supercritical fluid chromatography method was proposed for the separation of 10 target components including 8 furanocoumarins and 2 flavonoids. After detailed condition optimization, the 10 target compounds can be baseline separated on a Trefoil CEL1 (3.0 mm × 150 mm, 2.5 µm) column using gradient elution. A 0.07% (v/v) trifluoroacetic acid in ethanol was determined to be the most proper mobile phase for the separation of target compounds. The column temperature, back pressure, flow rate were set at 36 â„ƒ, 2000 psi, 1.0 mL min-1 to 1.4 mL min-1, respectively. The ten target compounds were analyzed within 24 min using the optimized conditions. Under the optimized conditions, all the target compounds showed good linearity with linear correlation coefficients higher than 0.995, and satisfactory recovery in the range of 83.52-112.92%. All these results showed that the developed ultra-high performance supercritical fluid chromatography method was reliable and effective. Finally, the application of the developed method to cosmetic, Psoraleae fructus and Angelicae dahuricae radix samples were presented. The results highlight the applicability of the ultra-high performance supercritical fluid chromatography method to the analysis of interested compounds in pharmaceutical and cosmetic samples.

Multidisciplinary approach for the management of term pregnancy complicated by Eisenmenger syndrome / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Pregnancy in patients with Eisenmenger syndrome (ES) is associated with high maternal mortality rates of 30%‒50%, or even up to 65% in the case of a cesarean section (Yuan, 2016). Here, we report a case of term pregnancy complicated with ES and severe pulmonary artery hypertension (PAH), which was managed by a multidisciplinary team (MDT) and resulted in an uncomplicated delivery via elective cesarean section. The goal of this study is to emphasize the importance of multidisciplinary approach in the management of pregnancy with ES, which can profoundly improve maternal and infant outcomes.

Spatial Distribution of Parvalbumin-Positive Fibers in the Mouse Brain and Their Alterations in Mouse Models of Temporal Lobe Epilepsy and Parkinson's Disease / 神经科学通报·英文版

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.

A comparative study of three chemometrics methods combined with excitation-emission matrix fluorescence for quantification of the bioactive compounds aesculin and aesculetin in Cortex Fraxini.

Cortex Fraxini is an important traditional Chinese herbal medicine with various medical functions. Aesculin and aesculetin are the main effective components of Cortex Fraxini. The fluorescence signals of the two compounds have a high degree of overlap with each other, making quantitative analysis difficult with conventional analytical methods. In the present study, different chemometrics methods, including lasso regression (LAR), interval partial least squares (iPLS), and multidimensional partial least squares (N-PLS) methods, were employed and combined with excitation-emission matrix (EEM) fluorescence for the purpose of accurate quantification of aesculin and aesculetin in Cortex Fraxini samples. The most satisfactory results were obtained by using the N-PLS method based on the EEM spectra without scatterings, with correlation coefficient of calibration and prediction values higher than 0.9972 and 0.9962, respectively, root mean squared errors for calibration and prediction values lower than 0.0304 and 0.1165, respectively, and recovery values in the range of 83.32%-104.62%. The obtained credible models indicated that the N-PLS method combined with EEM spectra has the advantages of being green, low cost, and accurate and it is a good strategy for the determination of active compounds in complex samples. To further confirm the accuracy of the obtained results, the same samples were analyzed by the recognized ultra-performance liquid chromatography method.

Simvastatin rescues memory and granule cell maturation through the Wnt/ß-catenin signaling pathway in a mouse model of Alzheimer's disease.

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/ß-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/ß-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the ß-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/ß-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/ß-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-ß-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.

A hybrid variable selection and modeling strategy for the determination of target compounds in different spectral datasets.

In this paper, a hybrid technique is proposed to establish quantitative models for the determination of target compounds in different spectral datasets. The proposed hybrid method is the hybridization of interval partial least squares (iPLS) method with gradient descent (GD) algorithm. Here, the novelty of the proposed method is that the iPLS method is applied to variable selection and the GD algorithm is employed to establish quantitative models based on the selected optimal variables. In the application of the hybrid iPLS-GD method, the factors, i.e., the number of the interval for the iPLS method and the learning rate, the number of iterations for the GD method, that affect the quantitative accuracy of the method are optimized and determined. Then three spectral datasets, including the near-infrared spectroscopy (NIR) dataset, nuclear magnetic resonance (1H NMR) dataset and excitation-emission matrix fluorescence (EEM) dataset, are used to test and verify the performance of the iPLS-GD method. We compare the hybrid iPLS-GD method with the PLS and iPLS methods from the aspects of modeling ability and predictive ability. The results demonstrated that the iPLS-GD method can be used as an effective and promising tool for the determination of target compounds in complex samples in practice.

Efficacy of robot-assisted arthroscopic anterior cruciate ligament reconstruction / 中华创伤杂志

Objective:To compare the clinical efficacy of robot-assisted and simple arthroscopic reconstruction of anterior cruciate ligament (ACL).Methods:A retrospective cohort study was conducted to analyze the clinical data of 37 patients with ACL tear admitted to Honghui Hospital of Xi′an Jiaotong University from January 2020 to September 2020. There were 24 males and 13 females, aged 16-45 years［(30.7±9.8)years］. A total of 17 patients were treated by robot-assisted ACL reconstruction (robot-assisted group), and 20 patients by simple arthroscopic ACL reconstruction (simple arthroscopy group). The operation time, number of guide wire drilling, positional accuracy of bone tunnel (distance between the central point of bone tunnel and ideal anatomical point) and perioperative complications were compared between the two groups. Knee stability was evaluated by Lachman test and KT-2000 measurement, and knee function by Lysholm score, International Knee Documentation Committee (IKDC) score and range of motion of joint flexion and extension before operation, at 4 months after operation and at the last follow-up.Results:All patients were followed up for 12-18 months［(13.1±4.1)months］. The operation time in robot-assisted group was (83.8±11.3)minutes, significantly longer than (50.4±9.1)minutes in simple arthroscopy group ( P<0.01). The number of guide wire drilling in robot-assisted group was (2.2±0.5)times, less than (2.5±0.4)times in simple arthroscopy group ( P<0.05). The distance between the central point of bone tunnel and ideal anatomical point was (1.3±0.3)mm in robot-assisted group, not significantly different from (1.4±0.3)mm in simple arthroscopy group ( P>0.05). There were no perioperative complications in both groups. The two groups showed no significant differences in Lachman test, KT-2000 measurement, Lysholm score, IKDC score and range of motion of joint flexion and extension before operation, at 4 months after operation and at the last follow-up (all P>0.05). The above indices in both groups were significantly improved at 4 months after operation and at the last follow-up as compared with those before operation (all P<0.01), and both groups showed no significant difference in the above indexes at 4 months after operation and at the last follow-up as compared with those before operation (all P>0.05). Conclusion:Compared with simple arthroscopic ACL reconstruction, robot-assisted ACL reconstruction can prepare a bone tunnel once with good location and direction in one time and achieve similar results in stability and functional recovery of the joint except for slightly longer operation time.

Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Development and validation of ultra-high performance supercritical fluid chromatography method for quantitative determination of six compounds in Guizhi Fuling capsule and tablet samples.

A fast and simple ultra-high performance supercritical fluid chromatography method has been developed for the determination of six analytes, namely (paeonol, coumarin, cinnamic alcohol, cinnamic acid, paeoniflorin, and amygdalin) in Guizhi Fuling capsule and tablet samples. The influence of the key chromatographic parameters for the separation purposes was evaluated. The optimal column was Trefoil CEL1 column. The optimal mobile phase was a gradient mixture of carbon dioxide and methanol at flow rate of 1.0 mL/min. The back pressure of the system was set to 1.38 × 107  Pa and the temperature to 45°C. The six compounds were separated within 11 min by the proposed ultra-high performance supercritical fluid chromatography method with satisfactory resolution. Method validation confirmed that the procedure is accurate with the recovery rates from 87.04 to 104.30%, intraday precision values less than 4.81% and interday precision less than 5.22%, and linear with R2 higher than 0.9967. Therefore, this work provides a simple and novel method for the simultaneous analysis of six compounds in Guizhi Fuling capsule and tablet samples.

Correlations between content of linarin in Chrysanthemum indicum and climatic factors in habitats / 中国中药杂志

Chrysanthemi Indici Flos(CIF), the capitulum of Chrysanthemum indicum, is widely used in proprietary Chinese medicine and daily chemical products. At present, CIF is mainly produced from wild resources and rarely cultivated. This study aims to reveal the correlations between linarin content in CIF and climatic factors in different habitats, and provide a theoretical basis for suitable zoning and rational production of medicinal materials. The content of linarin in CIF was determined by HPLC. Grey relational analysis and Pearson correlation analysis were carried out for linarin content with climatic factors. The results showed that the content of linarin in CIF was significantly different among different habitats. The grey relational degrees of climatic factors with linarin content was in an order of average annual precipitation>annual average sunshine hours>annual average temperature>longitude>annual frost-free period>latitude>altitude. Longitude, annual average temperature and average annual precipitation had significantly positive correlations with the content of linarin in CIF, whereas latitude and altitude showed negative correlations with it. The annual frost-free period and annual average sunshine hours had no significant correlation with the content of linarin in CIF. The content of linarin in CIF varied significantly in different habitats. High longitude, low latitude, low altitude, high annual average temperature and high annual average precipitation could be used as indicators for the habitats of high-quality Ch. indicum. This study provides a reference for selecting suitable producing areas of Ch. indicum and establishing artificial cultivation system.

Study on the mechanism of Dahuangfuzi decoction in improving intestinal motility disorder of rats with severe acute pancreatitis / 中华急诊医学杂志

Objective:To explore the mechanism of Dahuangfuzi decoction on intestinal motility disorder by observing its effect on serum motilin, Cajal interstitial cells and motilin receptor in rats with severe acute pancreatitis (SAP).Methods:Eighteen clean male Sprague-Dawley rats were randomly divided into the control group, SAP group and Dahuangfuzi group ( n=6 each group). The SAP rat model was prepared by retrogradely injected 4% sodium taurocholate into cholangiopancreatic duct. The rats in the SAP group were given 2 mL normal saline (37℃) enema at 12 and 24 h after operation. The rats in the Dahuangfuzi group was given 2 mL Dahuangfuzi decoction (37℃) enema at 12 and 24 h respectively. For the control group, the pancreas was exposed in the same way and then the abdomen was closed. Forty-eight h after operation, the abdominal aorta blood samples were taken for determination of serum endotoxin and amylase, and for detection of serum motilin by enzyme-linked immunosorbent assay (ELISA); the pathological changes of pancreas and ileum were observed by hematoxylin-eosin (HE) staining. The expression of c-kit and motilin receptor protein in ICC in ileum tissue was detected by immunohistochemistry. Results:Compared with the control group, the levels of serum endotoxin and amylase in the SAP group were significantly higher [(504.98±88.81) pg/mL vs. (17.76±5.01) pg/mL; (532.28±66.53) vs. (69.45±3.61) U/L, P<0.05], while the levels of serum motilin were significantly lower [(195.4±6.7) ng/L vs. (301±8.10) ng/L, P<0.05], and the scores of c-kit and motilin receptor protein were decreased ( P<0.05); compared with the SAP group, the levels of serum endotoxin and amylase in the Dahuangfuzi group were significantly reduced [(189.9±38.23) pg/mL vs. (504.98±88.81) pg/mL; (294.23±25.66) vs. (532.28±66.53) U/L, P<0.05], while the levels of serum motilin were significantly increased [(264.2±8.3) ng/L vs. (195.4±6.7) ng/L, P<0.05], and the scores of c-kit and motilin receptor protein were increased ( P<0.05). Conclusions:Dahuangfuzi decoction can improve the intestinal motility of SAP rats by promoting the secretion of motilin, increasing the activity of ICC cells and the expression of motilin receptor.

Efficacy of arthroscopic anchor fixation of medial collateral ligament combined with anterior and posterior cruciate ligament reconstruction in the treatment of type KD-IIIM dislocation of knee joint / 中华创伤杂志

Objective:To compare the clinical effect of anchor fixation of medial collateral ligament（MCL）and non-repaired treatment combined with arthroscopic anterior and posterior cruciate ligament reconstruction in the treatment of type KD-IIIM（Schenck classification）dislocation of knee joint.Methods:A retrospective case-control study was conducted to analyze the clinical data of 41 patients with type KD-IIIM dislocation of the knee joint admitted to Xi'an Honghui Hospital of Xi'an Jiaotong University from September 2015 to September 2017. There were 26 males and 15 females，with the age range of 15-62 years［（37.7±13.9）years］. A total of 21 patients were treated by arthroscopic anterior and posterior cruciate ligament reconstruction and anchor fixation of MCL（repaired group）and 20 patients by arthroscopic anterior and posterior cruciate ligament reconstruction without MCL repair（non-repaired group）. The perioperative complications were observed. Comparisons between the two groups were made before operation，4 months after operation and at the last follow-up in terms of Lysholm score，International Knee Documentation Committee（IKDC）score，Visual Analogue Scale（VAS）and range of motion of joint flextion and extension. The medial opening distance of stress X-ray of lower limbs was also observed at the last follow-up.Results:All patients were followed up for 48-66 months［（54.4±5.1）months］. No perioperative complications were noted. The Lysholm score，IKDC score，VAS and range of motion of joint flextion and extension showed no statistical differences between the two groups before operation（ P>0.05），and all were improved from the preoperative level at 4 months after operation and at the last follow-up（ P<0.05）. The Lysholm score in repaired group were（69.7±5.1）points and（83.8±4.9）points at 4 months after operation and at the last follow-up，significantly higher than those in non-repaired group［（61.0±5.5）points and（74.6±6.0）points］（ P<0.05）. The IKDC score in repaired group was（71.8±4.0）points at 4 months after operation，significantly higher than that in non-repaired group［（71.1±3.9）points］（ P<0.05）. The IKDC score in repaired group was（82.3±5.1）points at the last follow-up，similar with that in non-repaired group［（83.2±4.0）points］（ P>0.05）. The VAS in repaired group was（2.5±0.6）points at 4 months after operation，significantly decreased in comparison with（3.2±1.2）points in non-repaired group（ P<0.05）. The VAS in repaired group was（2.0±1.4）points when compared to（2.2±1.3）points in non-repaired group at the last follow-up（ P>0.05）. The range of motion of joint flextion and extension in repaired group was（107.6±6.9）° and（125.9±7.8）° at 4 months after operation and at the last follow-up，significantly increased in comparison with（89.6±4.0）° and（120.9±5.2）° in non-repaired group（ P<0.05）. The medial opening distance in repaired group was（2.3±0.2）mm at the last follow-up，significantly decreased when compared to（3.1±0.2）mm in non-repaired group（ P<0.05）. Conclusion:For type KD-IIIM knee dislocation，arthroscopic anchor fixation of MCL or without MCL repair combined with anterior and posterior cruciate ligament reconstruction are both effective in satisfactory functional recovery，but MCL repair contributes to earlier function recovery，faster pain relief and more reliable joint stability.

Identification of Prototype Components and Their Metabolites in Rat Serum, Urine and Feces After Oral Administration of Phellodendri Amurensis Cortex Aqueous Extract by UPLC-Orbitrap Fusion Lumos Tribrid-MS / 中国实验方剂学杂志

Objective:An ultra-performance liquid chromatography coupled with Orbitrap Fusion Lumos Tribrid mass spectrometry （UPLC-Orbitrap Fusion Lumos Tribrid-MS） was applied to analyze the prototypes and their metabolites of Phellodendri Amurensis Cortex aqueous extract in the serum， urine and feces of normal rats， and to investigate the pharmacodynamic material basis of Phellodendri Amurensis<italic> </italic>Cortex in rats. Method:Chromatographic separation was performed on the ACQUITY UPLC^® CSH^TM C₁₈ column （2.1 mm×100 mm， 1.7 μm） with the mobile phase of 0.1% formic acid aqueous solution （A）-acetonitrile （B） for gradient elution （0-15 min， 2%-25%B； 15-25 min， 25%-50%B； 25-28 min， 50%-98%B）， flow rate was 0.3 mL·min^-1， the injection volume was 10 μL and the column temperature was 40 ℃. Heated electrospray ionization （HESI） was used to collect data in the positive ion modes with the scanning range of <italic>m</italic>/<italic>z</italic> 100-1 000. By comparing chromatogram differences between the blank samples and the samples after administration， prototypes and their metabolites of biological samples after oral administration of Phellodendri Amurensis Cortex aqueous extract were identified. Result:After oral administration of Phellodendri Amurensis Cortex aqueous extract， a total of 70 compounds including 15 prototypes and 55 metabolites in rat serum， urine and feces were detected. Among them， 15 prototypes included 12 alkaloids and 3 limonoids， and 55 metabolites included 52 alkaloids and 3 limonoids. Desaturation， methylation， oxidation， sulfonation and glucuronide conjugation were observed as the primary metabolic pathways for the chemical constituents of Phellodendri Amurensis Cortex aqueous extract. Conclusion:Alkaloids in Phellodendri Amurensis Cortex aqueous extract undergo phase Ⅰ and phase Ⅱ metabolism in rats， and limonoids mainly undergo phase Ⅰ metabolism in rats. This paper can provide experimental basis for further analyzing the process <italic>in vivo</italic> of Phellodendri Amurensis Cortex and elucidating its pharmacodynamic substance basis<italic>.</italic>

Anti-scarring effect of rapamycin following filtering surgery in rabbit eyes / 南方医科大学学报

OBJECTIVE@#To study the effect of rapamycin on scar formation in rabbit eyes following filtering operation and explore the possible mechanism.@*METHODS@#Ninety-six healthy adult rabbits were subjected to trabeculectomy of the left eye and subsequently randomly divided into 4 groups (=24) for treatment with castor oil (control) or rapamycin (1%, 3%, or 5%) eye drops of the operated eyes 4 times a day. The morphology and function of the filtering blebs of the rabbits were compared at 7, 14, 21 and 28 days after the operation; at each of the time points, 6 rabbits from each group were euthanized for detection of expressions of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) in the tissues in the surgical area using immunohistochemistry. Cultured rabbit subconjunctival fibroblasts (RTFSs) were treated with different concentrations of rapamycin (0.06, 0.25, 1, and 4 mg/L) and the cell apoptosis was detected using flow cytometry.@*RESULTS@#In the first, second and third weeks after the operation, the rate of functional follicle formation was significantly higher in the 3 rapamycin groups than in the control group ( < 0.05), and the number of α- SMA-positive fibroblasts decreased over time in the 3 rapamycin groups. In cultured RTFSs, treatment with rapamycin at different concentrations resulted in increased apoptosis of the cells, and rapamycin above 0.25 mg/L significantly increased the cell apoptosis in a dose-dependent manner.@*CONCLUSIONS@#Rapamycin can inhibit hyperplasia of the filtering passage tissue, helps to preserve the functional filtering blebs and prolong their life span, and induces apoptosis of RTFS.

Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia.

Aerobic physical exercise (EX) and controlling cardiovascular risk factors in midlife can improve and protect cognitive function in healthy individuals and are considered to be effective at reducing late-onset dementia incidence. By investigating commonalities between these preventative approaches, we sought to identify possible targets for effective interventions. We compared the efficacy of EX and simvastatin (SV) pharmacotherapy to counteract cognitive deficits induced by a high-cholesterol diet (2%, HCD) in mice overexpressing TGF-ß1 (TGF mice), a model of vascular cognitive impairment and dementia. Cognitive deficits were found in hypercholesterolemic mice for object recognition memory, and both SV and EX prevented this decline. EX improved stimulus-evoked cerebral blood flow responses and was as effective as SV in normalizing endothelium-dependent vasodilatory responses in cerebral arteries. The up-regulation of galectin-3-positive microglial cells in white matter (WM) of HCD-fed TGF mice with cognitive deficits was significantly reduced by both SV and EX concurrently with cognitive recovery. Altered hippocampal neurogenesis, gray matter astrogliosis, or microgliosis did not correlate with cognitive deficits or benefits. Overall, results indicate that SV and EX prevented cognitive decline in hypercholesterolemic mice and that they share common sites of action in preventing endothelial cell dysfunction and reducing WM inflammation.-Trigiani, L. J., Royea, J., Tong, X.-K., Hamel, E. Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia.

High cholesterol triggers white matter alterations and cognitive deficits in a mouse model of cerebrovascular disease: benefits of simvastatin.

Transgenic mice overexpressing transforming growth factor-ß1 (TGF mice) display impaired cerebrovascular reactivity, cerebral hypoperfusion and neurovascular uncoupling, but no overt cognitive deficits until old age. Cardiovascular diseases are a major risk factor for vascular cognitive impairment and dementia (VCID). We investigated the impact of a high cholesterol diet (HCD) on cerebrovascular and cognitive function in adult (6 months) and aged (12 months) TGF mice, together with the potential benefit of simvastatin (SV), an anti-cholesterol drug with pleiotropic effects, in adult mice. HCD increased blood, but not brain, cholesterol levels in treated mice, which SV did not reduce. In WT mice, HCD induced small, albeit significant, impairment in endothelium-dependent dilatory function. In TGF mice, HCD worsened the established brain vessel dilatory dysfunction in an age-dependent manner and increased the number of string vessels in the white matter (WM), alterations respectively normalized and significantly countered by SV. HCD triggered cognitive decline only in TGF mice at both ages, a deficit prevented by SV. Concurrently, HCD upregulated galectin-3 immunoreactivity in WM microglial cells, a response significantly reduced in SV-treated TGF mice. Grey matter astrogliosis and microgliosis were not affected by HCD or SV. In the subventricular zone of adult HCD-treated TGF mice, SV promoted oligogenesis and migration of oligodendrocyte progenitor cells. The results demonstrate that an underlying cerebrovascular pathology increases vulnerability to cognitive failure when combined to another risk factor for dementia, and that WM alterations are associated with this loss of function. The results further indicate that myelin repair mechanisms, as triggered by SV, may bear promise in preventing or delaying cognitive decline related to VCID.

Pleiotropic Benefits of the Angiotensin Receptor Blocker Candesartan in a Mouse Model of Alzheimer Disease.

The angiotensin receptor blocker losartan mitigated cerebrovascular and cognitive deficits in mouse models of Alzheimer disease, in line with some clinical evidence of reduced onset and progression to Alzheimer disease. We investigated whether these benefits apply to another angiotensin receptor blocker, namely candesartan. Adult transgenic mice overexpressing a mutated form of the human APP (amyloid precursor protein) and wild-type controls were treated with vehicle or candesartan (cohort 1: 2 months, 1 mg/kg per day, osmotic subcutaneous minipumps; cohort 2: 5 months, 10 mg/kg per day in drinking water). Candesartan largely restored endothelial and smooth muscle function and reduced neuroinflammation in both cohorts, without improving sensory evoked cerebral blood flow responses. Candesartan exerted restorative effects on the reduced number of Ki67-immunopositive proliferating cells in the granule cell layer of the hippocampus but not on that of DCX (doublecortin)-positive immature granule cells, despite normalizing the length of their dendritic projections in the molecular layer. Amyloid plaque load and impaired cognitive function were unaltered by candesartan, and blood pressure was decreased in treated APP and wild-type mice. Overall, findings show that candesartan shared several advantages reported previously for losartan, but it exhibited limited cognitive benefits and stronger blood pressure lowering effects. The choice of angiotensin receptor blocker may thus be critical for therapeutic efficacy in patients with vascular diseases at high risk of developing Alzheimer disease.

Transforming growth factor-ß1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways.

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-ß1 (TGF-ß1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-ß1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-ß1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

Anti-scarring effect of rapamycin in rabbits following glaucoma filtering surgery / 南方医科大学学报

OBJECTIVE@#To study the anti- scarring effect of rapamycin in rabbits receiving glaucoma filtering surgery.@*METHODS@#Ninety-six Chinchilla rabbits were randomized equally into 3 rapamycin treatment groups and one control group. All the rabbits underwent trabeculectomy, after which the rabbits in the 3 rapamycin groups were treated with eye drops containing 1%, 3%, or 5% rapamycin in the operated eyes, and those in the control groups were given castor oil 4 times a day. The intraocular pressure (IOP) and inflammatory reaction in the treated eyes were observed, and the PCNA-positive cells in the filtering bleb were detected using immunohistochemistry. RTFs isolated from the Tenon's capsule of the rabbits were cultured , and the expressions of caspase-3, caspase-8, and caspase-9 in the fibroblasts were detected after treatment with different concentrations of rapamycin.@*RESULTS@#The IOP was significantly lower in rapamycin-treated group than in the control group after the surgery ( < 0.05). The counts of the PCNA-positive cells were significantly lower in rapamycin-treated rabbits than in the control group ( < 0.05). Rapamycin treatment dose-dependently increased the expressions of caspase-3 and caspase- 9 at both the mRNA ( < 0.001) and protein ( < 0.001) levels without causing significant changes in the expressions of caspase-8.@*CONCLUSIONS@#Rapamycin can inhibit excessive proliferation of the fibroblasts in the filtering bleb to reduce scar formation after glaucoma filtration surgery in rabbits. Rapamycin also increases the expressions of caspase-3 and caspase-9 to induce apoptosis of the RTFs.