scholarly journals TRPV4 inhibition prevents increased water diffusion and blood-retina barrier breakdown in the retina of streptozotocin-induced diabetic mice

2019 ◽  
Author(s):  
Maricruz Orduña Ríos ◽  
Ramsés Noguez Imm ◽  
Nicole Marilú Hernández Godínez ◽  
Ana María Bautista Cortes ◽  
Wolfgang Liedtke ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Retinal Thickness ◽  
Outer Nuclear Layer ◽  
Diabetic Mouse ◽  
Water Diffusion ◽  
Diabetic Mice ◽  
Retinal Edema ◽  
Ionic Homeostasis ◽  
Channel Inhibition ◽  
Brb Breakdown

AbstractA better understanding of the molecular and cellular mechanisms involved in retinal hydro-ionic homeostasis imbalance during diabetic macular edema (DME) is needed to gain insights into retinal physio(patho)logy that will help elaborating innovative therapies with lower health care costs. Transient receptor potential cation channel subfamily vanilloid member 4 (TRPV4) plays an intricate role in homeostatic processes that needs to be deciphered in normal and diabetic retina. Based on previous findings showing that TRPV4 antagonists resolve blood-retina barrier (BRB) breakdown in diabetic rats, we evaluated whether TRPV4 channel inhibition prevents and reverts retinal edema in streptozotocin(STZ)-induced diabetic mice. We assessed retinal edema using common metrics, including retinal morphology/thickness (histology) and BRB integrity (albumin-associated tracer), and also by quantifying water mobility through apparent diffusion coefficient (ADC) measures. ADC was measured by diffusion-weighted magnetic resonance imaging (DW-MRI), acquiredex vivoat 4 weeks after STZ injection in diabetes and control groups. DWI images were also used to assess retinal thickness. TRPV4 was genetically ablated or pharmacologically inhibited as follows: left eyes were used as vehicle control and right eyes were intravitreally injected with TRPV4-selective antagonist GSK2193874, 24 h before the end of the 4 weeks of diabetes. Histological data show that retinal thickness was similar in nondiabetic and diabetic wt groups but increased in diabeticTrpv4−/−mice. In contrast, DWI shows retinal thinning in diabetic wt mice that was absent in diabeticTrpv4−/−mice. Disorganized outer nuclear layer was observed in diabetic wt but not in diabeticTrpv4−/−retinas. We further demonstrate increased water diffusion and BRB hyperpermeability in diabetic wt mice, effects that were absent in diabeticTrpv4−/−mice. Retinas of diabetic mice treated with PBS showed increased water diffusion that was not inhibited by GSK2193874. ADC maps in nondiabeticTrpv4−/−mouse retinas showed restricted diffusion. Our data provide evidence that water diffusion is increased in diabetic mouse retinas and that TRPV4 function contributes to retinal hydro-ionic homeostasis and structure under control conditions, and to the development of BRB breakdown and increased water diffusion in the retina under diabetes conditions. A single intravitreous injection of TRPV4 antagonist is however not sufficient to revert these alterations in diabetic mouse retinas.

scholarly journals Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus

2018 ◽  
Vol 47 (4) ◽  
pp. 1365-1376 ◽  
Author(s):  
Jing Tong ◽  
Yan Lai ◽  
Yi-An Yao ◽  
Xue-Jun Wang ◽  
Yu-Shuang Shi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Diabetic Mouse ◽  
Transient Receptor Potential Vanilloid ◽  
Ang Ii ◽  
Diabetic Mice ◽  
Angiotensin Ii Receptor ◽  
Beneficial Effects

Background/Aims: To explore the potential role of qiliqiangxin (QLQX) A traditional Chinese medicine and the involvement of angiotensin II receptor type 1 (AGTR1) and transient receptor potential vanilloid 1 (TRPV1) in diabetic mouse cardiac function. Methods: Intragastric QLQX was administered for 5 weeks after streptozotocin (STZ) treatment. Additionally, Intraperitoneal injections of angiotensin II (Ang II) or intragastric losartan (Los) were administered to assess the activities of AGTR1 and TRPV1. Two-dimensional echocardiography and tissue histopathology were used to assess cardiac function Western blot was used to detect the autophagic biomarkers Such as light chain 3 P62 and lysosomal-associated membrane protein 2 And transmission electron microscopy was used to count the number of autophagosomes. Results: Decreased expression of TRPV1 and autophagic hallmarks and reduced numbers of autophagolysosomes as well as increased expression of angiotensin converting enzyme 1 and AGTR1 were observed in diabetic hearts. Blocking AGTR1 with Los mimicked the QLQX-mediated improvements in cardiac function Alleviated myocardial fibrosis and enabled autophagy Whereas Ang II abolished the beneficial effects of QLQX in wild type diabetic mice but not in TRPV1-/- diabetic mice. Conclusions: QLQX may improve diabetic cardiac function by regulating AGTR1/ TRPV1-mediated autophagy in STZ-induced diabetic mice.

Creation of retinal vein occlusion model in cynomolgusmonkeys and determination of its pathological features

2020 ◽  
Vol 17 ◽  
Author(s):  
Satoshi Inagaki ◽  
Masamitsu Shimazawa ◽  
Wataru Otsu ◽  
Tomoaki Araki ◽  
Yosuke Numata ◽  
...  
Keyword(s):  
Growth Factors ◽  
Retinal Vein Occlusion ◽  
Vascular System ◽  
Retinal Thickness ◽  
Chronic Phase ◽  
Vascular Leakage ◽  
Foveal Avascular Zone ◽  
Retinal Edema ◽  
Vein Occlusion ◽  
Angiopoietin 2

Objective: A retinal vein occlusion (RVO) is a relatively common retinal vascular disorder especially in the elder-ly. Many experiments have been performed on patients with a RVO but performing any type of experiments and especially longitudinal experiments on humans is difficult if not impossible on ethical grounds. Therefore, we have created a retinal vein occlusion (RVO) model by laser irradiation of cynomolgus monkeysafter an intravenous injection of rose bengal. Weevaluated the pathological changes of the retina, and the effects of ranibizumab, an anti-vascular endothelial growth factor (VEGF) antibody, on the characteristics of the RVO. Methods: The integrity of the vascular system was evaluated by fluorescein angiography (FA), and the retinal thickness and volume were determined by optical coherence tomography (OCT). The cytokines and growth factors in the aqueous humor were identified by multiplex profiling. Results: Our results showed that ranibizumab decreased the degree of vascular leakage and retinal edema at 1-3 days (acute phase) and 3-7 days (subacute phase), and suppressed foveal thinning at 28-42 days (chronic phase) after the laser irradia-tion. Ranibizumab also decreased the area of the foveal avascular zone, and the area was negatively and significantly corre-lated with the thickness of the ganglion cell layer (GCL) complex. Furthermore, ranibizumab reduced the increased expres-sion of VEGF in the aqueous humour, but did not affect the expressions of interleukin-6 (IL-6), monocyte chemotactic pro-tein-1 (MCP-1), angiopoietin-1 (ANG-1), or angiopoietin-2 (ANG-2).Thesefindings suggest that ranibizumab attenuates the retinal edema and subsequent retinal atrophy in partby neutralizing VEGF. However, other cytokines and growth factors were also affected by the ranibizumab which suggests that not only VEGF but also other unidentified agents might play a role in the pathogenesis of the RVO. Conclusion: We have created a non-human primate RVO model, which resembles the clinical RVO pathology. In this model, an injection of ranibizumab leads to a reduction in the vascular leakage and the retinal thickness and volume by blockingthe expression of VEGF. Our model might be useful for investigating the pathological mechanisms of RVOs and explore new therapeutic agents for RVO.

A mitochondria-targeted near-infrared fluorescent probe for imaging viscosity in living cells and a diabetic mice model

2021 ◽  
Author(s):  
Bochao Chen ◽  
Shumei Mao ◽  
Yanyan Sun ◽  
Liyuan Sun ◽  
Ning Ding ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fluorescent Probe ◽  
Near Infrared ◽  
Diabetic Mouse ◽  
Living Cells ◽  
Pancreatic Tissue ◽  
Diabetic Mice ◽  
Mice Model ◽  
Viscosity Changes

A mitochondria-targeted near-infrared fluorescent probe NIR-V with 700 nm emission was designed to monitor cell viscosity changes, which was applied to detect the intracellular viscosity and imagine pancreatic tissue in diabetic mouse model.

scholarly journals Therapeutic effects of Hypoxia-Inducible Factor-1α (HIF-1α) on bone formation around implants in diabetic mice

2018 ◽  
Author(s):  
Sang-Min Oh ◽  
Jin-Su Shin ◽  
Il-Koo Kim ◽  
Jae-Seung Moon ◽  
Jung-Ho Kim ◽  
...  
Keyword(s):  
Bone Formation ◽  
Rna Sequencing ◽  
Normal Mouse ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Diabetic Mouse ◽  
Differentially Expressed ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Hypoxia Inducible Factor 1Α

AbstractPatients with uncontrolled diabetes are susceptible to implant failure due to impaired bone metabolism. Hypoxia-Inducible Factor 1α (HIF-1α), a transcription factor that is up-regulated in response to reduced oxygen condition during the bone repair process after fracture or osteotomy, is known to mediate angiogenesis and osteogenesis. However, its function is inhibited under hyperglycemic conditions in diabetic patients. The aim of this study is to evaluate the effects of exogenous HIF-1α on bone formation around implants by applying HIF-1α to diabetic mice via a novel PTD-mediated DNA delivery system. Smooth surface implants (1mm in diameter; 2mm in length) were placed in the both femurs of diabetic and normal mice. HIF-1α and placebo gels were injected to implant sites of the right and left femurs, respectively: Normal mouse with HIF-1α gel (NH), Normal mouse with placebo gel (NP), Diabetic mouse with HIF-1α gel (DH), and Diabetic mouse with placebo gel (DP). RNA sequencing was performed 4 days after surgery. Based on RNA sequencing, Differentially Expressed Genes (DEGs) were identified and HIF-1α target genes were selected. Histologic and histomorphometric results were evaluated 2 weeks after the surgery. The results showed that bone-to-implant contact (BIC) and bone volume (BV) were significantly greater in the DH group than the DP group (p < 0.05). A total of 216 genes were differentially expressed in DH group compared to DP group. On the other hand, there were 95 DEGs in the case of normal mice. Twenty-one target genes of HIF-1α were identified in diabetic mice through bioinformatic analysis of DEGs. Among the target genes, NOS2, GPNMB, CCL2, CCL5, CXCL16 and TRIM63 were manually found to be associated with wound healing-related genes. In conclusion, local administration of HIF-1α via PTD may help bone formation around the implant and induce gene expression more favorable to bone formation in diabetic mice.

scholarly journals Induction of leukocyte adhesion molecules and renal physiologically active molecules in Porphyromonas gingivalis lipopolysaccharide-induced diabetic nephropathy

2020 ◽  
Author(s):  
Koichiro Kajiwara ◽  
Yoshihiko Sawa ◽  
Takahiro Fujita ◽  
Sachio Tamaoki
Keyword(s):  
Diabetic Nephropathy ◽  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Diabetic Mouse ◽  
Renal Parenchyma ◽  
Periodontal Pathogen ◽  
Diabetic Patients ◽  
Renal Tubules ◽  
Diabetic Mice ◽  
Leukocyte Adhesion Molecules

Abstract Background We recently reported that the glomerular endothelium expresses toll-like receptor (TLR)2 and TLR4 in diabetic environments and established that the TLR2 ligand Porphyromonas (P.) gingivalis lipopolysaccharides (LPS) induces nephropathy in diabetic mice. It is thought that P. gingivalis LPS promotes the chronic inflammation with the overexpression of leukocyte adhesion molecules and renal-specific metabolic enzymes by the recognition of P. gingivalis LPS via TLR in the diabetic kidneys. The present study aims to examine the expression of leukocyte adhesion molecules and renal metabolic factors in mouse kidneys with periodontal pathogen P. gingivalis LPS-induced diabetic nephropathy that was recently established. Methods The immunohistochemical investigation was performed on mouse kidney with P. gingivalis LPS-induced diabetic nephropathy model with glomerulosclerosis in glomeruli. Results There were no vessels which expressed vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or fibroblast growth factor (FGF) 23 in diabetic mice, or in healthy mice administered P. gingivalis LPS. However, in diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy the expression of VCAM-1 and the accumulation of FGF23 were established in renal tubules and glomeruli, and the expression of E-selectin was established in renal parenchyma and glomeruli. The angiotensin-converting enzyme 2 (ACE2) was detected in the proximal tubules but not in other regions including not in distal tubules of diabetic mice without LPS, and not in healthy mice administered P. gingivalis LPS. In diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy ACE2 was detected both in renal tubules as well as in glomeruli. The macrophage-1 (Mac-1) and podoplanin-positive cells increased in the renal parenchyma with diabetic condition and there was accumulation in P. gingivalis LPS-induced diabetic nephropathy. As the expression of VCAM-1 and E-selectin is upregulated in glomeruli, tubules, and intertubular capillaries, it is thought that the inflammatory infiltration of the monocyte-macrophage lineage promoted in kidneys with P. gingivalis LPS-induced the diabetic nephropathy. Conclusions P. gingivalis LPS may progressively accelerate the development of the renal inflammatory environment in LPS-accumulated glomeruli with the macrophage infiltration via the renal expression of VCAM-1 and E-selectin, and with ACE2 overexpression and FGF23 accumulation. Periodontitis may be a critical factor in the progress of nephropathy in diabetic patients.

Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

2018 ◽  
Vol 52 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Sisse A Nørgaard ◽  
Fredrik W Sand ◽  
Dorte B Sørensen ◽  
Klas SP Abelson ◽  
Henrik Søndergaard
Keyword(s):  
Weight Loss ◽  
Diabetic Nephropathy ◽  
Mouse Model ◽  
Diabetic Mouse ◽  
Diabetic Mice ◽  
Reduce Weight Loss ◽  
Normal Chow ◽  
Corticosterone Metabolites ◽  
Reducing Stress ◽  
Humane Endpoint

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

scholarly journals Inhibitory Effect of Manassantin B Isolated from Saururus chinensis on Skin Heat Aging

Cosmetics ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 47
Author(s):  
Hwa Sun Ryu ◽  
Jeong-Yeon Choi ◽  
Kyeong-Sun Lee ◽  
Jung-No Lee ◽  
Chun Mong Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Skin Aging ◽  
Shock Treatment ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Heat Shock Treatment ◽  
Channel Inhibition ◽  
Saururus Chinensis

Heat shock treatment-induced skin aging causes a thickened epidermis, increased matrix metalloproteinase (MMP)-1 expression, collagen degradation, and deep wrinkles. In this study, we investigated the effect of manassantin B in preventing heat shock treatment-induced aging. We first separated manassantin B (MB) from the roots of Saururus chinensis, and the structure was identified using 1H- and 13C-NMR spectroscopy. RT-PCR and western blotting were applied to investigate the anti-aging effect of manassantin B. Manassantin B decreased MMP-1 expression through transient receptor potential vanilloid (TRPV) 1 channel inhibition and significantly increased procollagen expression. In addition, manassantin B suppressed MAPK phosphorylation in a dose-dependent manner. Our results suggest that manassantin B, the active ingredient in S. chinensis, can be effectively used to inhibit heat shock treatment-induced skin aging.

scholarly journals Correlation between Macular Pigment Optical Density and Neural Thickness and Volume of the Retina

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 888
Author(s):  
Norihiro Nagai ◽  
Teru Asato ◽  
Sakiko Minami ◽  
Misa Suzuki ◽  
Hajime Shinoda ◽  
...  
Keyword(s):  
Optical Density ◽  
Retinal Thickness ◽  
Outer Nuclear Layer ◽  
Plexiform Layer ◽  
Macular Pigment ◽  
Inner Plexiform Layer ◽  
The Mean ◽  
Short Wavelength Light ◽  
The Impact ◽  
Adult Volunteers

Macular pigment (MP), which is composed of lutein/zeaxanthin/mezo-zeaxanthin, is concentrated in the central part of the retina, the macula. It protects the macula by absorbing short-wavelength light and suppressing oxidative stress. To evaluate whether MP levels are related to retinal neural protection and resulting health, we analyzed the association between the MP optical density (MPOD), and the macular thickness and volumes. Forty-three eyes of 43 healthy adult volunteers (21 men and 22 women; age: 22–48 (average 31.4 ± 1.1) years) were analyzed. Highly myopic eyes (<-6 diopters) were excluded. MPOD was measured using MPS2®, and the neural retinal thickness and volume were measured using optical coherence tomography. The mean MPOD was 0.589 ± 0.024, and it positively correlated with the central retinal thickness (P = 0.017, R = 0.360) and retinal volume of the fovea (1-mm diameter around the fovea; P = 0.029, R = 0.332), parafovea (1–3-mm diameter; P = 0.002, R = 0.458), and macula (6-mm diameter; P = 0.003, R = 0.447). In the macular area (diameter: 6 mm), MPOD was correlated with the retinal neural volume of the ganglion cell layer (P = 0.037, R = 0.320), inner plexiform layer (P = 0.029, R = 0.333), and outer nuclear layer (P = 0.020, R = 0.353). Thus, MPOD may help in estimating neural health. Further studies should determine the impact of MP levels on neuroprotection.

scholarly journals Extracellular histones induce calcium signals in the endothelium of resistance-sized mesenteric arteries and cause loss of endothelium-dependent dilation

2019 ◽  
Vol 316 (6) ◽  
pp. H1309-H1322 ◽  
Author(s):  
Daniel M. Collier ◽  
Nuria Villalba ◽  
Adrian Sackheim ◽  
Adrian D. Bonev ◽  
Zachary D. Miller ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Transient Receptor Potential ◽  
Prolonged Exposure ◽  
Vascular Dysfunction ◽  
Receptor Potential ◽  
Mesenteric Arteries ◽  
Transient Receptor Potential Vanilloid ◽  
Histone Proteins ◽  
Genetic Ablation ◽  
Channel Inhibition

Histone proteins are elevated in the circulation after traumatic injury owing to cellular lysis and release from neutrophils. Elevated circulating histones in trauma contribute to coagulopathy and mortality through a mechanism suspected to involve endothelial cell (EC) dysfunction. However, the functional consequences of histone exposure on intact blood vessels are unknown. Here, we sought to understand the effects of clinically relevant concentrations of histones on the endothelium in intact, resistance-sized, mesenteric arteries (MAs). EC Ca2+ was measured with high spatial and temporal resolution in MAs from mice selectively expressing the EC-specific, genetically encoded ratiometric Ca2+ indicator, Cx40-GCaMP-GR, and vessel diameter was measured by edge detection. Application of purified histone protein directly to the endothelium of en face mouse and human MA preparations produced large Ca2+ signals that spread within and between ECs. Surprisingly, luminal application of histones had no effect on the diameter of pressurized arteries. Instead, after prolonged exposure (30 min), it reduced dilations to endothelium-dependent vasodilators and ultimately caused death of ~25% of ECs, as evidenced by markedly elevated cytosolic Ca2+ levels (793 ± 75 nM) and uptake of propidium iodide. Removal of extracellular Ca2+ but not depletion of intracellular Ca2+ stores prevented histone-induced Ca2+ signals. Histone-induced signals were not suppressed by transient receptor potential vanilloid 4 (TRPV4) channel inhibition (100 nM GSK2193874) or genetic ablation of TRPV4 channels or Toll-like receptor receptors. These data demonstrate that histones are robust activators of noncanonical EC Ca2+ signaling, which cause vascular dysfunction through loss of endothelium-dependent dilation in resistance-sized MAs. NEW & NOTEWORTHY We describe the first use of the endothelial cell (EC)-specific, ratiometric, genetically encoded Ca2+ indicator, Cx40-GCaMP-GR, to study the effect of histone proteins on EC Ca2+ signaling. We found that histones induce an influx of Ca2+ in ECs that does not cause vasodilation but instead causes Ca2+ overload, EC death, and vascular dysfunction in the form of lost endothelium-dependent dilation.

scholarly journals Quetiapine Attenuates the Neuroinflammation and Executive Function Deficit in Streptozotocin-Induced Diabetic Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Kexin Wang ◽  
Feng Song ◽  
Hongxing Wang ◽  
Jun-hui Wang ◽  
Yu Sun
Keyword(s):  
Cognitive Deficit ◽  
Neuroprotective Effect ◽  
Underlying Mechanism ◽  
Diabetic Mouse ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Protein Loss ◽  
Monocyte Chemoattractant Protein 1 ◽  
Beneficial Effects ◽  
Increased Risk

Diabetic patients are at increased risk for developing memory and cognitive deficit. Prior studies indicate that neuroinflammation might be one important underlying mechanism responsible for this deficit. Quetiapine (QTP) reportedly exerts a significant neuroprotective effect in animal and human studies. Here, we investigated whether QTP could prevent memory deterioration and cognitive impairment in a streptozotocin- (STZ-) induced diabetic mouse model. In this study, we found that STZ significantly compromised the behavioral performance of mice in a puzzle box test, but administering QTP effectively attenuated this behavioral deficit. Moreover, our results showed that QTP could significantly inhibit the activation of astrocytes and microglia in these diabetic mice and reduce the generation and release of two cytokines, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). Meanwhile, QTP also prevented the protein loss of the synaptic protein synaptophysin (SYP) and myelin basic protein (MBP). Here, our results indicate that QTP could inhibit neuroinflammatory response from glial cells and block the injury of released cytokines to neurons and oligodendrocytes in diabetic mice (DM). These beneficial effects could protect diabetic mice from the memory and cognitive deficit. QTP may be a potential treatment compound to handle the memory and cognitive dysfunction in diabetic patients.

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