scholarly journals Efficacy of 670 nm Light Therapy to Protect against Photoreceptor Cell Death Is Dependent on the Severity of Damage

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Joshua A. Chu-Tan ◽  
Matt Rutar ◽  
Kartik Saxena ◽  
Yunlu Wu ◽  
Lauren Howitt ◽  
...  
Keyword(s):  
Cell Death ◽  
Photoreceptor Cell ◽  
Light Therapy ◽  
Sprague Dawley ◽  
Respiratory Capacity ◽  
Extracellular Flux ◽  
Sd Rats ◽  
Lower Light

Photobiomodulation at a wavelength of 670 nm has been shown to be effective in preventing photoreceptor cell death in the retina. We treated Sprague-Dawley (SD) rats with varying doses of 670 nm light (9; 18; 36; 90 J/cm2) before exposing them to different intensities of damaging white light (750; 1000; 1500 lux). 670 nm light exhibited a biphasic response in its amelioration of cell death in light-induced degenerationin vivo. Lower light damage intensities required lower doses of 670 nm light to reduce TUNEL cell death. At higher damage intensities, the highest dose of 670 nm light showed protection.In vitro, the Seahorse XFe96 Extracellular Flux Analyzer revealed that 670 nm light directly influences mitochondrial metabolism by increasing the spare respiratory capacity of mitochondria in 661 W photoreceptor-like cells in light damaged conditions. Our findings further support the use of 670 nm light as an effective treatment against retinal degeneration as well as shedding light on the mechanism of protection through the increase of the mitochondrial spare respiratory capacity.

scholarly journals P0884MYO-INOSITOL HEXAPHOSPHATE PEGYLATION IMPROVES BIOAVAILABILITY BUT REDUCES ITS ANTI-VASCULAR CALCIFICATION EFFECT IN RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
M Mar Pérez ◽  
Miguel David Ferrer Reynes ◽  
Joaquín Ortega-Castro ◽  
Firas Bassissi ◽  
Joan Perelló ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Density Functional ◽  
Inositol Phosphates ◽  
Crystal Surface ◽  
Density Functional Theory Calculations ◽  
Sprague Dawley ◽  
Inositol Hexaphosphate ◽  
Sd Rats

Abstract Background and Aims Vascular calcification (VC) is a major contributor to increased morbidity and mortality in End Stage Kidney Disease (ESKD) patients undergoing dialysis. SNF472, a salt of inositol hexaphosphate (InsP6), is a selective calcification inhibitor that interferes in the formation and growth of ectopic hydroxyapatite (HAP). SNF472 is currently in Phase 3 clinical trials for the treatment of calciphylaxis in ESKD patients on dialysis. Inositol-1,2,3,5-tetraphosphate-4,6-bisPEG100 (InsP4bisPEG or INS3001) results from the PEGylation of inositol tetraphosphate (InsP4) with polyethylene glycol (PEG) 100. Our aim was to compare the relative bioavailability of SNF472 and InsP4bisPEG and their efficacy in the inhibition of calcification in silico, in vitro and in vivo. Method Subcutaneous (10 mg/kg) pharmacokinetics of InsP4bisPEG and SNF472 were assessed in Sprague Dawley (SD) rats. To evaluate the adsorption binding affinity (Eads) of SNF472, InsP4bisPEG and other inositol phosphates to the HAP crystal surface, computational studies were performed using Density Functional Theory calculations with DMOL3 (MS2016). The in vitro efficacy of the compounds was evaluated using a pharmacodynamic assay to measure the calcification potential of human plasma. An in vivo efficacy study (calcification induced by 3 consecutives daily s.c. administrations of 150 kIU/kg vitamin D3) was performed with SD rats receiving s.c. vehicle, or equimolar doses (36 µmol/kg) of SNF472 or InsP4bisPEG once daily. Results The PEGylation of inositol tetraphosphate in positions 4 and 6 increased the exposure and t1/2 of the compound when given subcutaneously compared to SNF472. Molecular modelling revealed that SNF472 binds to the HAP surface with higher affinity than InsP4bisPEG and INSP4 (ΔEads=-352 kcal/mol for SNF472, ΔEads=-177 kcal/mol for InsP4bisPEG and ΔEads=-146 Kcal/mol for InsP4, taking inositol as reference). These results were correlated with the inhibition of calcium phosphate crystallization in plasma in vitro. SNF472 treated animals presented significantly lower calcium levels in aorta, which were 38% and 55% lower than placebo and InsP4bisPEG treated animals, respectively. Conclusion The differential pharmacokinetic profile of InsP4bisPEG (INS3001) does not translate into higher, but lower, efficacy than SNF472 against vascular calcification when comparing equimolar doses.

scholarly journals The absorption of oral morroniside in rats: In vivo, in situ and in vitro studies

2019 ◽  
Vol 69 (2) ◽  
pp. 287-296 ◽  
Author(s):  
Shan Xiong ◽  
Jinglai Li ◽  
Yanling Mu ◽  
Zhenqing Zhang
Keyword(s):  
Iridoid Glycosides ◽  
Specific Substrate ◽  
Sprague Dawley ◽  
Glycoprotein P ◽  
Cornus Officinalis ◽  
Sd Rats ◽  
Basolateral Side

Abstract Morroniside is one of the most important iridoid glycosides from Cornus officinalis Sieb. et Zucc. In the present study, the pharmacokinetics and bioavailability studies of morroniside were conducted on Sprague-Dawley (SD) rats. A rat in situ intestinal perfusion model was used to characterize the absorption of morroniside. Caco-2 cells were used to examine the transport mechanisms of morroniside. The pharmacokinetic study of morroniside exhibited linear dose-proportional pharmacokinetic characteristics and low bioavailability (4.3 %) in SD rats. Its average Peff value for transport across the small intestinal segments changed from (3.09 ± 2.03) × 10−6 to (4.53 ± 0.94) × 10−6 cm s−1. In Caco-2 cells, the Papp values ranged from (1.61 ± 0.53) × 10−9 to (1.19 ± 0.22) × 10−7 cm s−1 for the apical to basolateral side and the Pratio values at three concentrations were all lower than 1.2. Morroniside showed poor absorption and it might not be a specific substrate of P-glycoprotein (P-gp).

scholarly journals Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 409 ◽  
Author(s):  
Mi-Jin Choi ◽  
Hyunsook Kang ◽  
Yun Yeong Lee ◽  
Oak-Sung Choo ◽  
Jeong Hun Jang ◽  
...  
Keyword(s):  
Cell Death ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Sprague Dawley ◽  
Western Blots ◽  
Brainstem Response ◽  
Ganglion Neurons

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.

scholarly journals A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

2020 ◽  
Author(s):  
Tien-Tzu Tai ◽  
Tzung-Ju Wu ◽  
Huey-Dong Wu ◽  
Yi-Chen Tsai ◽  
Hui-Ting Wang ◽  
...  
Keyword(s):  
Animal Model ◽  
Targeted Delivery ◽  
Potential Treatment ◽  
Proof Of Concept ◽  
Sprague Dawley ◽  
Dosing Regimen ◽  
Sd Rats ◽  
Lower Blood

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 µg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 µg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (∼30-fold) lung exposure, longer (∼2.5-fold) half-life in lung, but lower blood exposure with ∼20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

scholarly journals Toll-Like Receptor 3 Activation Initiates Photoreceptor Cell Death In Vivo and In Vitro

2017 ◽  
Vol 58 (2) ◽  
pp. 801 ◽  
Author(s):  
Mei-Ling Gao ◽  
Kun-Chao Wu ◽  
Wen-Li Deng ◽  
Xin-Lan Lei ◽  
Lue Xiang ◽  
...  
Keyword(s):  
Cell Death ◽  
Photoreceptor Cell ◽  
Toll Like Receptor

scholarly journals Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2153
Author(s):  
Ming Yang ◽  
Kwok-Fai So ◽  
Wai-Ching Lam ◽  
Amy Cheuk Yin Lo
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Photoreceptor Cell ◽  
Vision Loss ◽  
Peripheral Vision ◽  
Cell Damage ◽  
Research Area ◽  
Night Vision

Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.

scholarly journals The Influence of Caerulomycin A on the Intestinal Microbiota in SD Rats

Marine Drugs ◽  
2020 ◽  
Vol 18 (5) ◽  
pp. 277
Author(s):  
Hongwei Zhang ◽  
Mengmeng Lan ◽  
Guodong Cui ◽  
Weiming Zhu
Keyword(s):  
High Throughput Sequencing ◽  
Intestinal Flora ◽  
Hypervariable Region ◽  
Sprague Dawley ◽  
16S Rdna Gene ◽  
Sd Rats ◽  
Anti Tumor Activity ◽  
Ring Core

Caerulomycin A (CRM A) is the first example of natural caerulomycins with a 2,2′-bipyridyl ring core and 6-aldoxime functional group from Streptomyces caeruleus and recently from marine-derived Actinoalloteichus cyanogriseus WH1-2216-6. Our previous study revealed that CRM A showed anti-tumor activity against human colorectal cancer (CRC) both in vitro and in vivo. Because some intestinal flora can affect the occurrence and development of CRC, the influence of CRM A on the intestinal flora is worthy of study in Sprague–Dawley (SD) rats. The high throughput sequencing of the V3-V4 hypervariable region in bacterial 16S rDNA gene results showed that the CRM A affected the diversity of intestinal flora of the SD rats treated with CRM A for 2, 3 and 4 weeks. Further analysis indicated that the abundance of genera Prevotella_1, Prevotellaceae_UCG-001, and Lactobacillus were increased while the that of genera Alloprevotella and Ruminiclostridium_1 were decreased. For the CRC related intestinal flora, the abundance of genera Bacteroides, Fusobacterium, Enterococcus, Escherichia-Shigella, Klebsiella, Streptococcus, Ruminococcus_2, and Peptococcus of SD rats treated with CRM A were decreased, while that of abundance of genera Bifidobacterium, Lactobacillus, Faecalibacterium, Blautia, Oscillibacter, and Clostridium were increased. The results indicated that CRM A could influence the intestinal flora by inhibiting some species of harmful flora and improving the beneficial bacteria in intestinal flora in the SD rats. The results may provide a new idea for revealing the mechanism of the anti-CRC activity of CRM A.

scholarly journals Prediction of Hepatic Clearance of Stereoselective Metabolism of Carvedilol in Liver Microsomes and Hepatocytes of Sprague-Dawley and Cytochrome P450 2D-Deficient Dark Agouti Rats

2019 ◽  
Vol 22 ◽  
pp. 72-84
Author(s):  
Masahiro Iwaki ◽  
Toshiro Niwa ◽  
Hiroyuki Tanaka ◽  
Atsushi Kawase ◽  
Hiroshi Komura
Keyword(s):  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Hepatic Clearance ◽  
Dark Agouti ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Stereoselective Metabolism ◽  
Sd Rats

Hepatic clearance (CLh) of carvedilol (CAR), which is eliminated via stereoselective metabolism by the CYP2D subfamily of cytochromes P450 (CYPs), was predicted using liver microsomes and hepatocytes from Sprague-Dawley (SD) rats and CYP2D-deficient Dark Agouti (DA) rats to determine the usefulness of prediction method. Plasma concentrations of CAR following intravenous injection to DA rats were higher than those in SD rats. The volume of distribution at steady state and total clearance (CLtot) of S-CAR were approximately two times greater than those of R-CAR in both strains. CLh predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CLh prediction using DA rat hepatocytes was nearly identical to the CLh observed in DA rats in vivo, and was lower than that in SD rats. The predicted CLh in vitro using hepatocytes correlated well with the observed CLtot in vivo, which is expected to be nearly the same as CLh. These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CLh of CAR than those using liver microsomes.

FORMULATION DEVELOPMENT OF ORLISTAT NANOCRYSTALS: IN VITRO CHARACTERIZATION AND IN VIVO STUDIES

INDIAN DRUGS ◽  
2021 ◽  
Vol 58 (11) ◽  
pp. 29-37
Author(s):  
Momin Munira ◽  
◽  
Apurva Kadam ◽  
Chintan Bhavsar ◽  
Anisha D’Souza
Keyword(s):  
Treatment Time ◽  
In Vivo Studies ◽  
High Density Lipoproteins ◽  
Control Group ◽  
Sprague Dawley ◽  
Formulation Development ◽  
Subsequent Increase ◽  
Sd Rats

Poor solubility of orlistat limits its luminal concentration and hence needs to be administered in higher doses, leading to drug related side effects. The aim of the present research was to investigate nanocrystallization approach to increase the solubility of orlistat using melt extrusion and high-pressure homogenization (HPH) methods. The effect of factors like type and amount of polymer, homogenization pressure and time, and number of cycles on orlistat solubility was investigated. A ~10-fold increase in the solubility of orlistat was attained using OPo11N with a subsequent increase in the dissolution rate of the drug. Poloxamer 188-orlistat nanocrystals (OPo11N) as compared to pure orlistat led to a decrease in T90%(20 mins for OPo11N and 51 mins for marketed sample). In vivo studies in female Sprague Dawley (SD) rats showed that post one month of oral administration the total cholesterol and low-density lipoproteins of female SD rats remained unchanged compared to the control group. The triglycerides content and high-density lipoproteins levels were significantly increased with increase in the treatment time i.e. 12 weeks compared to the group treated with pure orlistat drug. In conclusion, the NC approach could serve as an effective formulation strategy for solubility enhancement of orlistat.

Preparation of cultured astrocytes for x-ray microanalysis

1989 ◽  
Vol 47 ◽  
pp. 988-989
Author(s):  
N.K.R. Smith ◽  
K.E. Hunter ◽  
P. Mobley ◽  
L.P. Felpel
Keyword(s):  
Cultured Cells ◽  
Elemental Content ◽  
Elemental Distribution ◽  
Sprague Dawley ◽  
X Ray ◽  
Cultured Astrocytes ◽  
Freeze Dried ◽  
Ultimate Objective

Electron probe energy dispersive x-ray microanalysis (XRMA) offers a powerful tool for the determination of intracellular elemental content of biological tissue. However, preparation of the tissue specimen , particularly excitable central nervous system (CNS) tissue , for XRMA is rather difficult, as dissection of a sample from the intact organism frequently results in artefacts in elemental distribution. To circumvent the problems inherent in the in vivo preparation, we turned to an in vitro preparation of astrocytes grown in tissue culture. However, preparations of in vitro samples offer a new and unique set of problems. Generally, cultured cells, growing in monolayer, must be harvested by either mechanical or enzymatic procedures, resulting in variable degrees of damage to the cells and compromised intracel1ular elemental distribution. The ultimate objective is to process and analyze unperturbed cells. With the objective of sparing others from some of the same efforts, we are reporting the considerable difficulties we have encountered in attempting to prepare astrocytes for XRMA.Tissue cultures of astrocytes from newborn C57 mice or Sprague Dawley rats were prepared and cultured by standard techniques, usually in T25 flasks, except as noted differently on Cytodex beads or on gelatin. After different preparative procedures, all samples were frozen on brass pins in liquid propane, stored in liquid nitrogen, cryosectioned (0.1 μm), freeze dried, and microanalyzed as previously reported.

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