An evaluation of in vivo voltage-sensitive dyes: pharmacological side effects and signal-to-noise ratios after effective removal of brain-pulsation artifacts

2012 ◽  
Vol 108 (11) ◽  
pp. 2931-2945 ◽  
Author(s):  
T. H. Grandy ◽  
S. A. Greenfield ◽  
I. M. Devonshire
Keyword(s):  
Side Effects ◽  
In Vivo Studies ◽  
Blue Dye ◽  
Single Trial ◽  
Signal To Noise ◽  
Noise Characteristics ◽  
Bpa Removal ◽  
Voltage Sensitive Dyes ◽  
Pulsation Artifacts

In the current study, we investigated pharmacological side effects and signal-to-noise ratios (SNRs) of two commonly used voltage-sensitive dyes (VSDs): the blue dye RH-1691 (1 mg/ml) and the red dye di-4-ANEPPS (0.1 mg/ml), applied in vivo to the rat barrel cortex. Blue dyes are often favored over red dyes in in vivo studies due to their apparent superior SNR, partly because their fluorescence spectrum is farther away from the hemoglobin absorption spectrum, making them less prone to heartbeat-associated brain-pulsation artifacts (BPA). We implemented a previously reported template-based BPA removal algorithm and evaluated its applicability to di-4-ANEPPS before comparing characteristics of the two dyes. Somatosensory-evoked potentials (SEPs) were also recorded. Whereas SEPs recorded before and after application of di-4-ANEPPS failed to exhibit demonstrable differences, RH-1691 caused a significant and prolonged increase in SEP amplitude for several hours. In contrast, neither dye influenced the spontaneous cortical activity as assessed by the spectral content of the EEG. Both dyes turned out to be strikingly similar with respect to changes in fractional fluorescence as a function of SEP response amplitude, as well as regarding shot noise characteristics after removal of the BPA. Thus there is strong evidence that the increased SNR for RH-1691 is a consequence of an artificially increased signal. When applying an appropriate BPA removal algorithm, di-4-ANEPPS has proven to be suitable for single-trial in vivo VSD imaging (VSDI) and produces no detectable neurophysiological changes in the system under investigation. Taken together, our data argue for a careful re-evaluation of pharmacological side effects of RH-1691 and support the applicability of di-4-ANEPPS for stable single-trial in vivo VSDI recordings.

Pomegranate, its Components and Modern Deliverable Formulations as Potential Botanicals in the Prevention and Treatment of Various Cancers

2021 ◽  
Vol 18 ◽  
Author(s):  
Laila Hussein ◽  
Mostafa Gouda ◽  
Harpal S. Buttar
Keyword(s):  
Side Effects ◽  
Biological Tissues ◽  
Pomegranate Juice ◽  
In Vivo Studies ◽  
Lifestyle Modifications ◽  
Cellular Mechanisms ◽  
Double Blind ◽  
Prevention And Treatment

Abstract: Cancer is a global multifactorial disease consisting of over 200 types of cancers. It is well recognized that primary prevention is an effective way to fight cancers by using natural polyphenolic anticancer foods, vegetables and fruits, avoiding exposure to carcinogenic environment, smoking cessation, and through lifestyle modifications. The present review provides up to date information on the effects and functions of pomegranate juice and its bioactive components on the most widespread six cancer types. Pomegranate contains important polyphenolic compounds such as ellagitannins and punicalagin, with strong antioxidant ability for scavenging free radicals and producing metal-chelates in the biological tissues. The in vitro and in vivo studies suggests that antioxidant and anti-inflammation properties of pomegranate constitute have major antimutagenic and antiproliferative activities for regulating gene expression, modulating cellular mechanisms, and limiting the ability of cancers to metastasize. A limited number of clinical studies have suggested that pomegranate ingredients have the potential for the prevention and treatment of cancer, especially colorectal and prostate cancer. In cancer therapy, it remains a clinical dilemma to hit the right target without inducing side effects. The costly anticancer chemotherapies are often associated with drug resistance and serious side effects in vital organs, and noncancerous neighboring cells. It appears that the pomegranate based phytotherapies would be affordable and cost-effective for next generation non-pharmacologic anticancer remedies with lesser side effects. However, well-designed, randomized, double-blind, and multi-center studies are needed to establish the long-term safety, efficacy and dose schedules for orally deliverable pomegranate formulations.

scholarly journals Novel T7-modified pH-responsive targeted nanosystem for co-delivery of docetaxel and curcumin in the treatment of esophageal cancer

2020 ◽  
Author(s):  
Lian Deng ◽  
Xiongjie Zhu ◽  
Zhongjian Yu ◽  
Ying Li ◽  
Lingyu Qin ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Side Effects ◽  
High Efficiency ◽  
In Vivo Studies ◽  
Ph Responsive ◽  
Therapeutic Platform ◽  
Multiple Drugs ◽  
Esophageal Cancer Cells

Abstract Although single-drug chemotherapy is still an effective treatment for esophageal cancer, its long-term application is limited by severe side effects. Nanomedicines have increasingly attracted attention because of their good biological safety, targeting and high-efficiency loading of multiple drugs. Herein, we have developed a pH-responsive nanocarrier that has high affinity for the transferrin receptor, which is overexpressed by tumor cells. The system is capable of simultaneous delivery of the chemotherapy drug, docetaxel, and the Chinese Medicine, curcumin, for treatment of esophageal cancer. This novel T7-modified targeting nanosystem releases loaded drugs when exposed to the acidic microenvironment of the tumor, and exerts a synergistic anti-tumor effect, and T7-NP-DC with docetaxel and curcumin loading of 10% and 6.1%, respectively. In vitro and in vivo studies showed that improved anti-tumor efficacy could be obtained by loading docetaxel and curcumin into the T7-modified nanocarrierwithout obvious toxicity or side effects, compared to drug without nanocarrier. Furthermore, the nanocarriers conjugated with T7 short peptides were more readily taken up by esophageal cancer cells compared with normal cells.Together, our findings indicate that the materials can safely exert synergistic anti-tumor effects and provide an excellent therapeutic platform for combination therapy of esophageal cancer.

scholarly journals Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 180 ◽  
Author(s):  
Aroha B. Sánchez ◽  
Beatriz Clares ◽  
María J. Rodríguez-Lagunas ◽  
María J. Fábrega ◽  
Ana C. Calpena
Keyword(s):  
Side Effects ◽  
Redox State ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Histological Evaluation ◽  
Sodium Diclofenac ◽  
Cox 2

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs.

scholarly journals Host−guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy

2019 ◽  
Vol 116 (14) ◽  
pp. 6618-6623 ◽  
Author(s):  
Guocan Yu ◽  
Benyue Zhu ◽  
Li Shao ◽  
Jiong Zhou ◽  
Manik Lal Saha ◽  
...  
Keyword(s):  
Side Effects ◽  
Click Reaction ◽  
Tumor Model ◽  
Therapeutic Outcome ◽  
In Vivo Studies ◽  
Drug Resistant ◽  
Hydrophobic Core ◽  
Anticancer Efficacy ◽  
Tumor Accumulation

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.

scholarly journals A versatile genetic tool for post-translational control of gene expression in Drosophila melanogaster

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sachin Sethi ◽  
Jing W Wang
Keyword(s):  
Gene Expression ◽  
Side Effects ◽  
Translational Control ◽  
High Efficiency ◽  
Developmental Stages ◽  
Dynamic Range ◽  
In Vivo Studies ◽  
Control Of Gene Expression ◽  
Regulate Protein

Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages. We further show that this system can be used to control in vivo gene expression levels with low background, large dynamic range, and in a reversible manner without detectable side effects on the lifespan or behavior of the animal. Additionally, we engineered tools for chemically controlling gene expression (GAL80-DD) and recombination (FLP-DD). We demonstrate the applicability of this technology in manipulating neuronal activity and for high-efficiency sparse labeling of neuronal populations.

scholarly journals Altered cortical processing of sensory input in Huntington disease mouse models

2021 ◽  
Author(s):  
Marja D Sepers ◽  
James P Mackay ◽  
Ellen Koch ◽  
Dongsheng Xiao ◽  
Majid H Mohajerani ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Cortical Neurons ◽  
Neurodegenerative Disorder ◽  
Ex Vivo ◽  
Sensory Stimulation ◽  
In Vivo Studies ◽  
Field Potentials ◽  
Sensory Responses ◽  
Voltage Sensitive Dyes

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.

scholarly journals A New Calcium Oral Controlled-Release System Based on Zeolite for Prevention of Osteoporosis

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2467 ◽  
Author(s):  
Angela Fabiano ◽  
Anna Maria Piras ◽  
Vincenzo Calderone ◽  
Lara Testai ◽  
Lorenzo Flori ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Calcium Ions ◽  
Rank Order ◽  
In Vivo Studies ◽  
Current Therapy ◽  
Effective Prevention ◽  
Prevention Of Osteoporosis

Osteoporosis, a systemic skeleton disease, can be prevented by increasing calcium levels in serum via administration of calcium salts. However, traditional calcium-based formulations have not appeared to be effective, hence the purpose of the present work has been to prepare and test in vitro/vivo a formulation able to gradually release calcium during transit over the GI tract, thus increasing bioavailability and reducing daily dose, and hence, side effects. Calcium controlled-release granules based on zeolite and Precirol® were prepared. In the best case, represented by granules sized 1.2 mm, containing 20% Precirol®, 19% zeolite, 60% calcium (granule), the release lasted ≈6 h. The release is controlled by diffusion of calcium ions through the aqueous channels forming within granules, once these come into contact with physiological fluids. Such a diffusion is hindered by the interaction of calcium ions with the negatively charged surface of the zeolite. Ovariectomy was used to make rats osteopenic. For in vivo studies, rats were divided into the following groups. Sham: not treated; ova: ovariectomized (ova); CaCl2 1.0 g: ova, treated with 1.0 g/die Ca2+; CaCl2 0.5 g: ova, treated with 0.5 g/die Ca2+; granule 1.0 g, or granule 0.5 g: ova, treated with granules equivalent to 1.0 g/die or 0.5 g/die Ca2+ in humans. Ca2+ amounts in femur bone and bone marrow, femur mechanical characteristics, and femur medullary canalicule diameter were measured and the same efficacy rank order was obtained: ova < CaCl2 0.5 g < CaCl2 1.0 g < granule 0.5 g ≈ granule 1.0 g ≈ sham. The results show promise of an effective prevention of osteoporosis, based on a controlled-rate administration of a calcium dose half that administered by the current therapy, with reduced side effects.

scholarly journals Antimicrobial Photodynamic Therapy Protocols on Streptococcus mutans with Different Combinations of Wavelengths and Photosensitizing Dyes

2019 ◽  
Vol 6 (2) ◽  
pp. 42
Author(s):  
Elisabetta Merigo ◽  
Stefania Conti ◽  
Tecla Ciociola ◽  
Maddalena Manfredi ◽  
Paolo Vescovi ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Diode Laser ◽  
Streptococcus Mutans ◽  
Toluidine Blue ◽  
Culture Media ◽  
Bactericidal Effect ◽  
In Vivo Studies ◽  
Blue Dye ◽  
532 Nm

The aim of the study is to test the application of different laser wavelengths, with and without different photosensitizing dyes on different types of cultures. Laser irradiation was realized on Streptococcus mutans in both solid and liquid culture media in continuous mode at three different fluences (10, 20, and 30 J/cm2) with a red diode (650 nm) with toluidine blue dye, a blue-violet diode (405 nm) with curcumin dye, and a green diode (532 nm) with erythrosine dye. Without a photosensitizer, no growth inhibition was obtained with the red diode at any fluence value. Inhibition rates of 40.7% and 40.2% were obtained with the blue diode and green diode. The blue diode laser used with curcumin obtained results in terms of growth inhibition up to 99.26% at a fluence of 30 J/cm2. The red diode laser used with toluidine blue obtained results in terms of growth inhibition up to 100% at fluences of 20 and 30 J/cm2. The KTP (potassium-titanyl-phosphate) laser used with erythrosine was able to determine a complete growth inhibition (100%) at the different fluence values. The combination of a laser and its proper color may dramatically change the results in terms of bactericidal effect. It will be interesting to confirm these data by further in vivo studies.

scholarly journals SCIDOT-28. TARGETED NANOPARTICLES FOR IMPROVED DRUG DELIVERY TO MEDULLOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi277-vi277
Author(s):  
Joelle P Straehla ◽  
Natalie Boehnke ◽  
Tamara G Dacoba ◽  
Paula T Hammond
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Side Effects ◽  
Tumor Cells ◽  
Chemical Engineering ◽  
Xenograft Model ◽  
In Vivo Studies ◽  
Layer By Layer

Abstract Platinum-based agents remain a key component of therapy for children with medulloblastoma, despite significant systemic side effects and only modest blood-brain barrier (BBB) penetration. Cisplatin has a cerebrospinal fluid-to-plasma ratio <5% and dose-limiting side effects of nephrotoxicity, ototoxicity, and myelosuppression. Improving delivery of cisplatin across the BBB and selectively accumulating in tumors could improve its therapeutic index. To this end, we are leveraging chemical engineering techniques to rationally design cisplatin nanoparticles (NPs) to cross the BBB and preferentially enter medulloblastoma tumor cells. Using the layer-by-layer (LbL) platform to ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we screened six negatively charged polypeptide and polysaccharide outer layers in medulloblastoma cell lines. Poly-L-aspartic acid (PLD) layered NPs had significant accumulation in tumor cells after 24 hours incubation, with an uptake index of 18±4 over unlayered control NPs. Next, we generated propargyl-functionalized PLD and used click chemistry to covalently conjugate the BBB shuttle ligands glutathione, angiopep-2, and transferrin, which have been shown to mediate transcytosis across brain endothelial cells. PLD layered NPs functionalized with angiopep-2 and transferrin had enhanced uptake in medulloblastoma tumor cells and NPs functionalized with glutathione were non-inferior to PLD layered NPs. After incubation with endothelial cells in vitro, all three BBB shuttle ligands enhanced uptake of PLD layered NPs over unlayered and non-functionalized control NPs. We then incorporated cisplatin into the nanoparticle core of this platform. Cisplatin-loaded NPs with PLD layering and ligand functionalization were more effective than free cisplatin as measured by IC50 over 72 hours in culture, and led to faster apoptosis as assessed by flow cytometry with annexin V and propidium iodide staining. In summary, functionalized nanoparticles are a promising platform to modulate drug delivery to medulloblastoma. In vivo studies using an orthotopic xenograft model are underway to investigate biodistribution, efficacy, and toxicity.

Ursolic and Oleanolic Acids as Potential Anticancer Agents Acting in the Gastrointestinal Tract

2018 ◽  
Vol 16 (1) ◽  
pp. 78-91 ◽  
Author(s):  
Mateusz Pięt ◽  
Roman Paduch
Keyword(s):  
Gastrointestinal Tract ◽  
Side Effects ◽  
Anticancer Agents ◽  
In Vivo Studies ◽  
Pentacyclic Triterpenoids ◽  
Liver Cancers ◽  
Anti Cancer ◽  
Tumorigenic Activity

Background:Cancer is one of the main causes of death worldwide. Contemporary therapies, including chemo- and radiotherapy, are burdened with severe side effects. Thus, there exists an urgent need to develop therapies that would be less devastating to the patient’s body. Such novel approaches can be based on the anti-tumorigenic activity of particular compounds or may involve sensitizing cells to chemotherapy and radiotherapy or reducing the side-effects of regular treatment.Objective:Natural-derived compounds are becoming more and more popular in cancer research. Examples of such substances are Ursolic Acid (UA) and Oleanolic Acid (OA), plant-derived pentacyclic triterpenoids which possess numerous beneficial properties, including anti-tumorigenic activity.Results:In recent years, ursolic and oleanolic acids have been demonstrated to exert a range of anticancer effects on various types of tumors. These compounds inhibit the viability and proliferation of cancer cells, prevent their migration and metastasis and induce their apoptosis. Both in vitro and in vivo studies indicate that UA and OA are promising anti-cancer agents that can prevent carcinogenesis at each step. Furthermore, cancers at all stages are susceptible to the activity of these compounds. </P><P> Neoplasms that are formed in the gastrointestinal tract, i.e. gastric, colorectal, pancreatic, and liver cancers, are among the most common and most lethal malignancies. Their localization in the digestive system, however, facilitates the action of orally-administered (potential) anti-cancer agents, making chemopreventive drugs more accessible.In this paper, the anti-tumorigenic effect of ursolic and oleanolic acids on gastric, colon, pancreatic, and liver cancers, as well as the mechanisms underlying this process, are presented.

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