Blocking Ocular Sympathetic Activity Inhibits Choroidal Neovascularization

Purpose: To investigate how modulating ocular sympathetic activity affects progression of choroidal neovascularization (CNV), a hallmark feature of wet age-related macular degeneration (AMD).Methods: In the first of two studies, Brown Norway rats underwent laser-induced CNV and were assigned to one of the following groups: daily eye drops of artificial tears (n = 10; control group); daily eye drops of the β-adrenoreceptor agonist isoproterenol (n = 10); daily eye drops of the β-adrenoreceptor antagonist propranolol (n = 10); sympathetic internal carotid nerve (ICN) transection 6 weeks prior to laser-induced CNV (n = 10). In the second study, rats underwent laser-induced CNV followed by ICN transection at different time points: immediately after the laser injury (n = 6), 7 days after the laser injury (n = 6), and sham surgery 7 days after the laser injury (n = 6; control group). All animals were euthanized 14 days after laser application. CNV development was quantified with fluorescein angiography and optical coherence tomography (in vivo), as well as lesion volume analysis using 3D confocal reconstruction (postmortem). Angiogenic growth factor protein levels in the choroid were measured with ELISA.Results: In the first study, blocking ocular sympathetic activity through pharmacological or surgical manipulation led to a 75% or 70% reduction in CNV lesion volume versus the control group, respectively (P < 0.001). Stimulating ocular sympathetic activity with isoproterenol also led to a reduction in lesion volume, but only by 27% versus controls (P < 0.05). VEGF protein levels in the choroid were elevated in the three treatment groups (P < 0.01). In the second study, fluorescein angiography and CNV lesion volume analysis indicated that surgically removing the ocular sympathetic supply inhibited progression of laser-induced CNV, regardless of whether ICN transection was performed on the same day or 7 days after the laser injury.Conclusion: Surgical and pharmacological block of ocular sympathetic activity can inhibit progression of CNV in a rat model. Therefore, electrical block of ICN activity could be a potential bioelectronic medicine strategy for treating wet AMD.

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The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats

Journal of Ophthalmology ◽

10.1155/2017/6145651 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13

Author(s):

Chengda Ren ◽

Hui Shi ◽

Juanjuan Jiang ◽

Qingyu Liu ◽

Yaru Du ◽

...

Keyword(s):

Choroidal Neovascularization ◽

Rat Model ◽

Kinase Inhibitor ◽

Pigment Epithelium ◽

Total Concentration ◽

Retinal Pigment ◽

Brown Norway ◽

Control Group ◽

Fundus Fluorescein Angiography ◽

Liquid Chromatography Tandem Mass

The aims of this study were to evaluate the effects of CM082 on the development of choroidal neovascularization (CNV) in a laser-induced CNV rat model and to determine the drug concentration in the ocular tissues. After the laser-induced CNV model was established in rats, CM082 was orally administered. The effects of CM082 on the CNV lesions were assessed using fundus fluorescein angiography (FFA), CNV histology, and retinal pigment epithelium- (RPE-) choroid-sclera eyecup analysis. The concentrations of CM082 in the plasma and eye tissues were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results of FFA, histology, and RPE-choroid-sclera eyecup analysis demonstrated that the CM082-treated (10 mg/kg/d or 30 mg/kg/d) rats exhibited significantly less neovascularization than did the control group. The total concentration of CM082 in the eyes (172.86 ± 57.11 ng/g) was similar to that in the plasma (196.87 ± 73.13 ng/ml). Within the eye, the concentrations of CM082 and its metabolites were highest in the retina-sclera. The orally administered CM082 thus effectively passed through the blood-retina barrier (BRB) to reach the retina in the Brown Norway rats. Therefore, at both 10 mg/kg/d and 30 mg/kg/d, CM082 was able to reduce CNV lesions in the laser-induced CNV rat model.

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Conjugated Linoleic Acid Causes a Marked Increase in Liver α-Tocopherol and Liver α-Tocopherol Transfer Protein in C57BL/6 J Mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000007 ◽

2010 ◽

Vol 80 (1) ◽

pp. 65-73 ◽

Cited By ~ 10

Author(s):

Pei-Min Chao ◽

Wan-Hsuan Chen ◽

Chun-Huei Liao ◽

Huey-Mei Shaw

Keyword(s):

Antioxidant Enzymes ◽

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Thiobarbituric Acid ◽

Control Group ◽

Thiobarbituric Acid Reactive Substances ◽

Control Groups ◽

Protein Levels ◽

Transfer Protein ◽

And Control

Conjugated linoleic acid (CLA) is a collective term for the positional and geometric isomers of a conjugated diene of linoleic acid (C18:2, n-6). The aims of the present study were to evaluate whether levels of hepatic α-tocopherol, α-tocopherol transfer protein (α-TTP), and antioxidant enzymes in mice were affected by a CLA-supplemented diet. C57BL/6 J mice were divided into the CLA and control groups, which were fed, respectively, a 5 % fat diet with or without 1 g/100 g of CLA (1:1 mixture of cis-9, trans-11 and trans-10, cis-12) for four weeks. α-Tocopherol levels in plasma and liver were significantly higher in the CLA group than in the control group. Liver α-TTP levels were also significantly increased in the CLA group, the α-TTP/β-actin ratio being 2.5-fold higher than that in control mice (p<0.01). Thiobarbituric acid-reactive substances were significantly decreased in the CLA group (p<0.01). There were no significant differences between the two groups in levels of three antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase). The accumulation of liver α-tocopherol seen with the CLA diet can be attributed to the antioxidant potential of CLA and the ability of α-TTP induction. The lack of changes in antioxidant enzyme protein levels and the reduced lipid peroxidation in the liver of CLA mice are due to α-tocopherol accumulation.

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Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity

International Journal of Molecular Sciences ◽

10.3390/ijms22094953 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4953

Author(s):

Natalie M. Zahr ◽

Kilian M. Pohl ◽

Allison J. Kwong ◽

Edith V. Sullivan ◽

Adolf Pfefferbaum

Keyword(s):

White Matter ◽

Proinflammatory Cytokines ◽

Soluble Protein ◽

Subcortical White Matter ◽

Control Group ◽

White Matter Volume ◽

Brain Volumes ◽

Protein Levels ◽

Matter Volume ◽

Patient Groups

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.

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Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

Cells ◽

10.3390/cells10071712 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1712

Author(s):

Roberta Magliozzi ◽

Francesco Pezzini ◽

Mairi Pucci ◽

Stefania Rossi ◽

Francesco Facchiano ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Cell ◽

Protein Pattern ◽

Fold Change ◽

Cortical Lesion ◽

Control Group ◽

Lesion Volume ◽

Mri Features ◽

Csf Levels ◽

Multiple Sclerosis Patients

An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1β, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-β, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.

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YAP1 Overexpression Is Associated with Kidney Dysfunction in Lupus Nephritis

Pathobiology ◽

10.1159/000517575 ◽

2021 ◽

pp. 1-12

Author(s):

Ying Xie ◽

Yuanyuan Ruan ◽

Huimei Zou ◽

Yixin Wang ◽

Xin Wu ◽

...

Keyword(s):

Lupus Nephritis ◽

Epithelial Mesenchymal Transition ◽

Kidney Tissue ◽

Mouse Kidney ◽

Experimental Comparison ◽

Control Group ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Protein Levels

Objective: The goal of the present study was to determine the expression of yes-associated protein 1 (YAP1) in renal tissues of mice with lupus nephritis (LN) and elucidate its role in the progression of renal fibrosis. Methods: C57BL/6 mice and MRL/lpr mice were selected for experimental comparison. Mouse kidney tissues were removed and sectioned for hematoxylin and eosin staining, Masson’s trichome staining, Sirius staining, and immunohistochemistry. The mRNA and protein levels of YAP1 in mouse kidney tissues were detected, and the correlation between YAP1 and fibronectin (FN) mRNA levels was analyzed. Mouse renal epithelial cells were used for in vitro experiments. After transfection and stimulation, the cells were divided into 4 groups, namely the C57BL/6 serum group (group 1), the MRL/lpr serum group (group 2), the MRL/lpr serum + siRNA-negative control group (group 3), and the MRL/lpr serum + siRNA-YAP1 group (group 4). Epithelial-mesenchymal transition (EMT) markers in each group were detected by Western blotting and immunofluorescence staining. Serum creatinine, blood urea nitrogen, and urinary protein levels were detected and assessed for their correlation with YAP1 mRNA levels by Spearman’s analysis. Results: Compared to C57BL/6 mice, MRL/lpr mice exhibited obvious changes in fibrosis in renal tissues. In addition, YAP1 expression was significantly higher in the renal tissues of MRL/lpr mice than in those of C57BL/6 mice, and YAP1 mRNA levels were positively correlated with those of FN. YAP1 silencing in lupus serum-stimulated cells could effectively relieve serum-induced EMT. Finally, we observed that YAP1 mRNA levels in mouse kidney tissue were significantly and positively correlated with the degree of renal function injury. Conclusion: YAP1 expression in the kidney tissues of LN mice was higher than that observed in normal mice, indicating that YAP1 may play an important role in the occurrence and development of LN.

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Aneuploid abortion correlates positively with MAD1 overexpression and miR-125b down-regulation

Molecular Cytogenetics ◽

10.1186/s13039-021-00538-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Juan Zhao ◽

Hui Li ◽

Guangxin Chen ◽

Lijun Du ◽

Peiyan Xu ◽

...

Keyword(s):

Chromosome Segregation ◽

Spindle Assembly Checkpoint ◽

Mitotic Checkpoint ◽

Early Embryo ◽

Vital Role ◽

Control Group ◽

Embryo Abortion ◽

Protein Levels ◽

Mitotic Checkpoint Complex

Abstract Background Aneuploidy is the most frequent cause of early-embryo abortion. Any defect in chromosome segregation would fail to satisfy the spindle assembly checkpoint (SAC) during mitosis, halting metaphase and causing aneuploidy. The mitotic checkpoint complex (MCC), comprising MAD1, MAD2, Cdc20, BUBR1 and BUB3, plays a vital role in SAC activation. Studies have confirmed that overexpression of MAD2 and BUBR1 can facilitate correct chromosome segregation and embryo stability. Research also proves that miR-125b negatively regulates MAD1 expression by binding to its 3′UTR. However, miR-125b, Mad1 and Bub3 gene expression in aneuploid embryos of spontaneous abortion has not been reported to date. Methods In this study, embryonic villi from miscarried pregnancies were collected and divided into two groups (aneuploidy and euploidy) based on High-throughput ligation-dependent probe amplification (HLPA) and Fluorescence in situ hybridization (FISH) analyses. RNA levels of miR-125b, MAD1 and BUB3 were detected by Quantitative real-time PCR (qRT-PCR); protein levels of MAD1 and BUB3 were analysed by Western blotting. Results statistical analysis (p < 0.05) showed that miR-125b and BUB3 were significantly down-regulated in the aneuploidy group compared to the control group and that MAD1 was significantly up-regulated. Additionally, the MAD1 protein level was significantly higher in aneuploidy abortion villus, but BUB3 protein was only mildly increased. Correlation analysis revealed that expression of MAD1 correlated negatively with miR-125b. Conclusion These results suggest that aneuploid abortion correlates positively with MAD1 overexpression, which might be caused by insufficient levels of miR-125b. Taken together, our findings first confirmed the negative regulatory mode between MAD1 and miR-125b, providing a basis for further mechanism researches in aneuploid abortion.

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Cardiac Parasympathetic Withdrawal and Sympathetic Activity: Effect of Heat Exposure on Heart Rate Variability

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18115934 ◽

2021 ◽

Vol 18 (11) ◽

pp. 5934

Author(s):

Oriol Abellán-Aynés ◽

Pedro Manonelles ◽

Fernando Alacid

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Environmental Conditions ◽

Sympathetic Activity ◽

Heat Exposure ◽

Repeated Measurements ◽

Control Group ◽

Poincaré Plot ◽

Activity Effect ◽

And Control

(1) Background: Research on heart rate variability has increased in recent years and the temperature has not been controlled in some studies assessing repeated measurements. This study aimed to analyze how heart rate variability may change based on environmental temperature during measurement depending on parasympathetic and sympathetic activity variations. (2) Methods: A total of 22 volunteers participated in this study divided into an experimental (n = 12) and control group (n = 10). Each participant was assessed randomly under two different environmental conditions for the experimental group (19 °C and 35 °C) and two identical environmental conditions for the control group (19 °C). During the procedure, heart rate variability measurements were carried out for 10 min. (3) Results: Significantly changes were observed for time and frequency domains as well as Poincaré plot variables after heat exposure (p < 0.05). These findings were not observed in the control group, whose conditions between measurements did not change. (4) Conclusions: The reduction of heart rate variability due to exposure to hot conditions appears to be produced mostly by a parasympathetic withdrawal rather than a sympathetic activation. Therefore, if consecutive measurements have to be carried out, these should always be done under the same temperature conditions.

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Effects of post-interventional antiplatelet therapy on angiographic vasospasm, delayed cerebral ischemia, and clinical outcome after aneurysmal subarachnoid hemorrhage: a single-center experience

Neurosurgical Review ◽

10.1007/s10143-021-01477-6 ◽

2021 ◽

Author(s):

Claudia Ditz ◽

Björn Machner ◽

Hannes Schacht ◽

Alexander Neumann ◽

Peter Schramm ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Functional Outcome ◽

Antiplatelet Therapy ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Control Group ◽

Lesion Volume ◽

Single Center ◽

Single Center Experience

AbstractPlatelet activation has been postulated to be involved in the pathogenesis of delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to investigate potentially beneficial effects of antiplatelet therapy (APT) on angiographic CVS, DCI-related infarction and functional outcome in endovascularly treated aSAH patients. Retrospective single-center analysis of aSAH patients treated by endovascular aneurysm obliteration. Based on the post-interventional medical regime, patients were assigned to either an APT group or a control group not receiving APT. A subgroup analysis separately investigated those APT patients with aspirin monotherapy (MAPT) and those receiving dual treatment (aspirin plus clopidogrel, DAPT). Clinical and radiological characteristics were compared between groups. Possible predictors for angiographic CVS, DCI-related infarction, and an unfavorable functional outcome (modified Rankin scale ≥ 3) were analyzed. Of 160 patients, 85 (53%) had received APT (n = 29 MAPT, n = 56 DAPT). APT was independently associated with a lower incidence of an unfavorable functional outcome (OR 0.40 [0.19–0.87], P = 0.021) after 3 months. APT did not reduce the incidence of angiographic CVS or DCI-related infarction. The pattern of angiographic CVS or DCI-related infarction as well as the rate of intracranial hemorrhage did not differ between groups. However, the lesion volume of DCI-related infarctions was significantly reduced in the DAPT subgroup (P = 0.011). Post-interventional APT in endovascularly treated aSAH patients is associated with better functional outcome at 3 months. The beneficial effect of APT might be mediated by reduction of the size of DCI-related infarctions.

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Long-term treadmill training ameliorates endothelium-dependent vasorelaxation mediated by insulin and insulin-like growth factor-1 in hypertension

Journal of Applied Physiology ◽

10.1152/japplphysiol.01062.2014 ◽

2015 ◽

Vol 119 (6) ◽

pp. 663-669 ◽

Cited By ~ 6

Author(s):

Yi-Yuan Lin ◽

Shin-Da Lee ◽

Chia-Ting Su ◽

Tsung-Lin Cheng ◽

Ai-Lun Yang

Keyword(s):

Growth Factor ◽

Insulin Receptor ◽

Treadmill Training ◽

Control Group ◽

Insulin Like Growth Factor ◽

Hypertensive Rats ◽

Protein Levels ◽

Significant Difference ◽

Nos Inhibitors

Dysfunction of insulin and insulin-like growth factor-1 (IGF-1) is associated with the pathophysiology of hypertension. The influence of long-term exercise on vascular dysfunction caused by hypertension remains unclear. We investigated whether long-term treadmill training improved insulin- and IGF-1-mediated vasorelaxation in hypertensive rats. Eight-week-old male spontaneously hypertensive rats (SHR) were randomly divided into sedentary and exercise (SHR-EX) groups. The SHR-EX group was trained on a treadmill for 60 min/day, 5 days/wk, for 8 wk. Wistar-Kyoto rats (WKY) were used as the normal control group. After training, aortic insulin- and IGF-1-mediated vasorelaxation was evaluated in organ baths. Additionally, the roles of phosphatidylinositol 3-kinase (PI3K), nitric oxide synthase (NOS), and aortic protein expression were examined in the three groups. Compared with sedentary SHR and WKY groups, insulin- and IGF-1-mediated vasorelaxation was significantly enhanced to a nearly normal level in the SHR-EX group. After endothelial denudation, blunted and comparable vasorelaxation was found among the three groups. Pretreatment with selective PI3K and NOS inhibitors attenuated insulin- and IGF-1-mediated vasorelaxation, and no significant difference was found among the three groups after the pretreatment. The aortic protein levels of the insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate-1 (IRS-1), and endothelial NOS (eNOS) were also significantly increased in the SHR-EX group compared with the other two groups. These results suggested that treadmill training elicited the amelioration of endothelium-dependent insulin/IGF-1-mediated vasorelaxation partly via the increased activation of PI3K and NOS, as well as the enhancement of protein levels of IR, IGF-1R, IRS-1, and eNOS, in hypertension.

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Increased S100B Levels in Cannabis Use Disorder

European Addiction Research ◽

10.1159/000442046 ◽

2015 ◽

Vol 22 (4) ◽

pp. 177-180 ◽

Cited By ~ 2

Author(s):

Huseyin Bayazit ◽

Erdinc Cicek ◽

Salih Selek ◽

Nurten Aksoy ◽

I. Fatih Karababa ◽

...

Keyword(s):

Calcium Binding ◽

Neuronal Damage ◽

Cannabis Use ◽

S100b Protein ◽

Control Group ◽

Blood Levels ◽

Cannabis Use Disorder ◽

Protein Levels ◽

S100 Calcium Binding Protein ◽

The Mean

Background: It has been determined that cannabis has adverse effects on brain tissue, and that increased S100 calcium binding protein B (S100B) blood levels are markers of neuronal damage. Therefore, the aim of this study was to evaluate the S100B levels in cannabis use disorder. Method: Thirty-two patients with cannabis use disorder and 31 matched healthy controls were enrolled in this study. Appropriate blood samples were taken from the enrolled subjects, and the serum S100B protein levels were measured with an electrochemiluminescence immunoassay for the quantification of the protein. Findings: We found significantly increased S100B protein levels in patients with cannabis use disorder. The mean serum concentration of S100B was 0.081 ± 0.018 μg/l in patients with cannabis use disorder, and 0.069 ± 0.018 μg/l in the control group (p = 0.008). Interpretation: Our data suggest that elevated S100B protein levels might indicate neuronal damage in the brains of people with cannabis use disorder.

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