scholarly journals Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. F. Zainullina ◽  
Yu. V. Vakhitova ◽  
A. Yu. Lusta ◽  
T. A. Gudasheva ◽  
S. B. Seredenin
Keyword(s):  
Animal Studies ◽  
Neuronal Cell ◽  
Maximum Effect ◽  
Protective Mechanisms ◽  
Protective Properties ◽  
Neurotrophic Activity ◽  
Low Weight ◽  
Pharmacokinetic Properties ◽  
Survival Mechanisms

AbstractBrain-derived neurotrophic factor (BDNF) is involved in the regulation of neuronal cell growth, differentiation, neuroprotection and synaptic plasticity. Although aberrant BDNF/TrkB signaling is implicated in several neurological, neurodegenerative and psychiatric disorders, neurotrophin-based therapy is challenging and is limited by improper pharmacokinetic properties of BDNF. Dimeric dipeptide compound GSB-106 (bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide) has earlier been designed to mimic the TrkB-interaction 4 loop of BDNF. It displayed protective effect in various cell-damaging models in vitro. Animal studies uncovered antidepressive and neuroprotective properties upon GSB-106 per os administration. Current study shows that GSB-106 acts similarly to BDNF, promoting survival of serum-deprived neuronal-like SH-SY5Y cells. 100 nmol concentration of GSB-106 provided maximum neurotrophic effect, which corresponds to about 37% of the maximum effect provided by BDNF. Protective properties of GSB-106 arise from its ability to counteract cell apoptosis via activation of TrkB-dependent pro-survival mechanisms, including inactivation of pro-apoptotic BAD protein and suppression of caspases 9 and 3/7. Thus, our study has characterized neurotrophic activity of small dimeric compound GSB-106, which mimics certain biological functions of BDNF and neurotrophin-specific protective mechanisms. GSB-106 also displays similarities to some known low weight peptide and non-peptide TrkB ligands.

Interactions of antidepressants, mood-stabilisers and antipsychotics with food

2019 ◽  
Vol 35 (1) ◽  
pp. 51-74
Author(s):  
Anna Wasik ◽  
Anna Krupa ◽  
Marcin Siwek
Keyword(s):  
Animal Studies ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Taste Perception ◽  
Dependent Manner ◽  
Quetiapine Xr ◽  
Pharmacokinetic Properties ◽  
Dose Dependent ◽  
Specific Food ◽  
Induce Weight Gain

Aim: The aim of the paper was to review and analyse the literature addressing interactions between food and antidepressants, mood stabilisers and antipsychotics. Literature review: The observed food and drug interactions are mutual and might lead to a decrease of the therapeutic effect, an increase of the drug toxicity or changes in the nutritional status. Drug and food interactions can modify the pharmacokinetic (e.g. absorption, metabolism) and/or pharmacodynamic properties of drugs. The food intake alters the absorption of trazodone XR, sulpiride, ziprasidone, lurasidone and quetiapine XR. Coffee, tea and possibly turmeric influence CYP1A2 in a dose-dependent manner. Fruit juices (grapefruit, Seville orange, blueberry), curcumin and piperine inhibit CYP3A4. In human studies, significant interactions between food and sertraline, clomipramine, clozapine and carbamazepine were found. Food containing tyramine was shown to interact with MAO inhibitors altering their pharmacodynamic properties. Both malnutrition and obesity may have an impact on the pharmacokinetic properties of some mood stabilisers and antipsychotics. On other hand, the majority of antipsychotics, mood stabilisers and some antidepressants induce weight gain. Changes in taste perception can occur during pharmacotherapy with some antidepressants (tricyclics, selective serotonin reuptake inhibitors), antipsychotics (risperidone) and mood-stabilisers (lithium, valproate). Conclusions: Appropriate care and consideration must be taken when attempting to extrapolate results of in vitro or animal studies to humans. To evaluate the clinical significance of a specific food and drug interaction, it might be necessary to measure the concentration of the pharmaceutical compound and its metabolites in blood serum.

scholarly journals Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis

2020 ◽  
Vol 21 (5) ◽  
pp. 1797 ◽  
Author(s):  
Hannes Glaß ◽  
Patrick Neumann ◽  
Arun Pal ◽  
Peter Reinhardt ◽  
Alexander Storch ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Animal Studies ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
Retrograde Transport ◽  
Spinal Neurons ◽  
Lyn Kinase ◽  
Neuronal Subtype ◽  
Induced Pluripotent

Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lyn-kinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease.

Decellularized bone extracellular matrix in skeletal tissue engineering

2020 ◽  
Vol 48 (3) ◽  
pp. 755-764
Author(s):  
Benjamin B. Rothrauff ◽  
Rocky S. Tuan
Keyword(s):  
Tissue Engineering ◽  
Bone Regeneration ◽  
Tissue Regeneration ◽  
Animal Studies ◽  
Tumor Resection ◽  
Regenerative Capacity ◽  
Skeletal Tissue ◽  
Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

Synthesis, Antimalarial Evaluation and SAR Study of Some 1,3,5-Trisubstituted Pyrazoline Derivatives

2019 ◽  
Vol 16 (10) ◽  
pp. 807-817 ◽  
Author(s):  
Shilpy Aggarwal ◽  
Deepika Paliwal ◽  
Dhirender Kaushik ◽  
Girish Kumar Gupta ◽  
Ajay Kumar
Keyword(s):  
Antimalarial Activity ◽  
Analysis Data ◽  
Docking Study ◽  
Maximum Activity ◽  
Elemental Analysis Data ◽  
Mass Spectral ◽  
Structure Activity ◽  
Pharmacokinetic Properties ◽  
Sar Study

The synthesis of a novel series of 1,3,5-trisubstitiuted pyrazoline was achieved by refluxing chalcone derivative with different heteroaryl hydrazines. The newly synthesized compounds were characterized by 1H NMR, 13CNMR, mass spectral and elemental analysis data. The synthetic series of novel pyrazoline hybrids was screened for in vitro schizont maturation assay against chloroquine sensitive 3D7 strain of Plasmodium falciparum. Most of the compounds showed promising in vitro antimalarial activity against CQ sensitive strain. The preliminary structure-activity relationship study showed that quinoline substituted analog at position N-1 showed maximum activity followed by benzothiazole substitution, while phenyl substitution lowers the antimalarial activity. The observed activity was persistent by the docking study on P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction.

In-vitro Kinetic Hydrolysis Study of Metronidazole Derivatives with Carvacrol and Eugenol Using Validated RP-HPLC Method

2020 ◽  
Vol 16 ◽  
Author(s):  
M. Alarjah
Keyword(s):  
Half Life ◽  
Hplc Method ◽  
Hydrolysis Rate ◽  
First Order ◽  
First Order Kinetics ◽  
Rp Hplc ◽  
Pharmacokinetic Properties ◽  
Pseudo First Order ◽  
Kinetic Hydrolysis

Background: Prodrugs principle is widely used to improve the pharmacological and pharmacokinetic properties of some active drugs. Much effort was made to develop metronidazole prodrugs to enhance antibacterial activity and or to improve pharmacokinetic properties of the molecule or to lower the adverse effects of metronidazole. Objective: In this work, the pharmacokinetic properties of some of monoterpenes and eugenol pro metronidazole molecules that were developed earlier were evaluated in-vitro. The kinetic hydrolysis rate constants and half-life time estimation of the new metronidazole derivatives were calculated using the validated RP-HPLC method. Method: Chromatographic analysis was done using Zorbbax Eclipse eXtra Dense Bonding (XDB)-C18 column of dimensions (250 mm, 4.6 mm, 5 μm), at ambient column temperature. The mobile phase was a mixture of sodium dihydrogen phosphate buffer of pH 4.5 and methanol in gradient elution, at 1ml/min flow rate. The method was fully validated according to the International Council for Harmonization (ICH) guidelines. The hydrolysis process carried out in an acidic buffer pH 1.2 and in an alkaline buffer pH 7.4 in a thermostatic bath at 37ºC. Results: The results followed pseudo-first-order kinetics. All metronidazole prodrugs were stable in the acidic pH, while they were hydrolysed in the alkaline buffer within a few hours (6-8 hr). The rate constant and half-life values were calculated, and their values were found to be 0.082- 0.117 hr-1 and 5.9- 8.5 hr., respectively. Conclusion: The developed method was accurate, sensitive, and selective for the prodrugs. For most of the prodrugs, the hydrolysis followed pseudo-first-order kinetics; the method might be utilised to conduct an in-vivo study for the metronidazole derivatives with monoterpenes and eugenol.

Protective Effect of Isothiocyanates from Cruciferous Vegetables on Breast Cancer: Epidemiological and Preclinical Perspectives

2020 ◽  
Vol 20 ◽  
Author(s):  
Suong N.T. Ngo ◽  
Desmond B. Williams
Keyword(s):  
Breast Cancer ◽  
Protective Effect ◽  
Animal Studies ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Human Studies ◽  
In Vitro Studies ◽  
Cochrane Library ◽  
Cruciferous Vegetables

Background: The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their antibreast cancer effects. Objective: The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer. Methods: A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peerreviewed studies of all types (in vitro studies, animal studies, and human studies) were selected. Results: The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways which promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemoresistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively smallest inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article. Conclusion: Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane appeared to display the greatest potential.

scholarly journals Optimal Initial Positioning of Chest Tubes to Prevent Retained Hemothorax Using a Novel Steerable Chest Tube With Extendable Infusion Cannula

2021 ◽  
Vol 186 (Supplement_1) ◽  
pp. 324-330
Author(s):  
John B Fortune ◽  
Serena Murphy ◽  
Kimberley Tiller
Keyword(s):  
Chest Tube ◽  
Animal Studies ◽  
Training Session ◽  
Penetrating Trauma ◽  
Pleural Space ◽  
Tube Placement ◽  
Clot Lysis ◽  
Retained Hemothorax ◽  
Tip Position

ABSTRACT Introduction With blunt and penetrating trauma to the chest, warfighters and civilians frequently suffer from punctured lung (pneumothorax) and/or bleeding into the pleural space (hemothorax). Optimal management of this condition requires the rapid placement of a chest tube to evacuate as much of the blood and air as possible. Incomplete drainage of blood leading to retained hemothorax may be the result of the final tube tip position not being in contact with the blood collections. To address this problem, we sought to develop a “steerable” chest tube that could be accurately placed or repositioned into a specific desired position in the pleural space to assure optimal drainage. An integrated infusion cannula was added for the instillation of anticoagulants to maintain tube patency, thrombolytics for clot lysis, and analgesics for pain control if required. Materials and Methods A triple-lumen tube was designed to provide a channel for a pull-wire which was wound around an axle integrated into a small proximal handle and controlled by a ratcheted thumbwheel. Tension on the wire creates an arc on the tube that allows for positioning. In vitro testing focused on the relationship between the tension on the pull-wire and the resultant arc. Two adult cadavers and two anesthetized pigs were used to study the feasibility of accurate tube placement. After a brief training session, providers were asked to place tubes inferiorly along the diaphragm where blood was anticipated to accumulate or at the apex of the lung for pneumothorax. Success was determined with fluoroscopic images and was judged as a tube tip lying in the targeted position. Results The design was prototyped with an extruded polyvinyl chloride multilumen tube and a 3D printed tensioning handle. In vitro studies showed that one turn of the thumbwheel created 70° to 90° of arc of the tube. Cadaver and animal studies showed consistent success in the desired placement of the tube at or near the lateral diaphragm or in the apex. Attempts were also successful by surgical residents with minimal training. Conclusions Initial preliminary studies on a novel steerable chest tube have demonstrated the ability to appropriately position the tube in a desired location. The addition of an extendable cannula will allow for safe clot lysis or maintained tube patency. Additional studies are planned to confirm the benefit of this device in preventing retained hemothorax.

The Use of Biomarkers as Alternatives to Current Animal Tests on Food Chemicals

1998 ◽  
Vol 26 (4) ◽  
pp. 421-480
Author(s):  
Krys Bottrill
Keyword(s):  
Animal Studies ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
In Vitro Test ◽  
Animal Testing ◽  
Dietary Biomarkers ◽  
Recent Developments ◽  
Mechanistic Basis ◽  
The Three Rs

Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.

scholarly journals Graphene-Doped Poly (Methyl-Methacrylate) (Pmma) Implants: A Micro-CT and Histomorphometrical Study in Rabbits

2021 ◽  
Vol 22 (3) ◽  
pp. 1441
Author(s):  
Antonio Scarano ◽  
Tiziana Orsini ◽  
Fabio Di Carlo ◽  
Luca Valbonetti ◽  
Felice Lorusso
Keyword(s):  
Methyl Methacrylate ◽  
Dental Implant ◽  
Animal Studies ◽  
White Male ◽  
Biological Response ◽  
Medullary Canal ◽  
Poly Methyl Methacrylate ◽  
Titanium Surfaces ◽  
Dental Applications

Background—the graphene-doping procedure represents a useful procedure to improve the mechanical, physical and biological response of several Polymethyl methacrylate (PMMA)-derived polymers and biomaterials for dental applications. The aim of this study was to evaluate osseointegration of Graphene doped Poly(methyl methacrylate) (GD-PMMA) compared with PMMA as potential materials for dental implant devices. Methods—eighteen adult New Zealand white male rabbits with a mean weight of approx. 3000 g were used in this research. A total of eighteen implants of 3.5 mm diameter and 11 mm length in GD-PMMA and eighteen implants in PMMA were used. The implants were placed into the articular femoral knee joint. The animals were sacrificed after 15, 30 and 60 days and the specimens were evaluated by µCT and histomorphometry. Results—microscopically, all 36 implants, 18 in PMMA and 18 in DG-PMMA were well-integrated into the bone. The implants were in contact with cortical bone along the upper threads, while the lower threads were in contact with either newly formed bone or with marrow spaces. The histomorphometry and µCT evaluation showed that the GP-PMMA and PMMA implants were well osseointegrated and the bone was in direct contact with large portions of the implant surfaces, including the space in the medullary canal. Conclusions—in conclusion, the results suggest that GD-PMMA titanium surfaces enhance osseointegration in rabbit femurs. This encourages further research to obtain GD-PMMA with a greater radiopacity. Also, further in vitro and vivo animal studies are necessary to evaluate a potential clinical usage for dental implant applications.

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