JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model

2022 ◽  
pp. 1-18
Author(s):  
Jessica L. Dennison ◽  
Claude-Henry Volmar ◽  
Danbing Ke ◽  
James Wang ◽  
Emilie Gravel ◽  
...  
Keyword(s):  
Oral Formulation ◽  
Related Gene ◽  
Male And Female ◽  
Beneficial Effects ◽  
Gene And Protein Expression ◽  
Cytokine Levels ◽  
Pharmacokinetic Properties ◽  
Brain Exposure ◽  
High Concentrations ◽  
Ad Mouse Model

Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROLTM, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

scholarly journals Natural Sources, Pharmacokinetics, Biological Activities and Health Benefits of Hydroxycinnamic Acids and Their Metabolites

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2190 ◽  
Author(s):  
Matej Sova ◽  
Luciano Saso
Keyword(s):  
Biological Activities ◽  
Health Benefits ◽  
Hydroxycinnamic Acids ◽  
Target Tissue ◽  
Natural Sources ◽  
Beneficial Effects ◽  
Specific Effects ◽  
Pharmacokinetic Properties ◽  
Natural Phenolic Compounds ◽  
High Concentrations

Hydroxycinnamic acids (HCAs) are important natural phenolic compounds present in high concentrations in fruits, vegetables, cereals, coffee, tea and wine. Many health beneficial effects have been acknowledged in food products rich in HCAs; however, food processing, dietary intake, bioaccessibility and pharmacokinetics have a high impact on HCAs to reach the target tissue in order to exert their biological activities. In particular, metabolism is of high importance since HCAs’ metabolites could either lose the activity or be even more potent compared to the parent compounds. In this review, natural sources and pharmacokinetic properties of HCAs and their esters are presented and discussed. The main focus is on their metabolism along with biological activities and health benefits. Special emphasis is given on specific effects of HCAs’ metabolites in comparison with their parent compounds.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

scholarly journals A32 EMPAGLIFOZIN IMPROVES GASTROINTESTINAL INFLAMMATION IN A MOUSE MODEL OF COLITIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 213-215
Author(s):  
K Madsen ◽  
H Dang ◽  
N Hotte ◽  
V Mocanu ◽  
M Ferdaoussi ◽  
...  
Keyword(s):  
Animal Model ◽  
Sglt2 Inhibitor ◽  
Direct Effects ◽  
Lipocalin 2 ◽  
Wild Type ◽  
Gut Inflammation ◽  
Beneficial Effects ◽  
Histological Score ◽  
Cytokine Levels ◽  
Gastrointestinal Inflammation

Abstract Background Empagliflozin (EMPA) is a highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor and is increasingly being utilized as an antihyperglycemic agent in the management of type 2 diabetes. Interestingly, it has been demonstrated in human trials that EMPA treatment exerts potent cardioprotective effects by reducing cardiac inflammation independently of glycemic control. Further, EMPA has also been shown to suppress LPS-induced renal and systemic inflammation in an animal model. Based on these findings, we hypothesized that EMPA treatment may also be effective in reducing gut inflammation. Aims The aim of this study was to examine the effects of treatment with EMPA on gastrointestinal inflammation in an animal model of inflammatory bowel disease and to determine mechanistic insights regarding its direct effects on gut cytokine secretion. Methods Adult male and female IL-10-/- mice with established colitis were treated with a daily gavage of EMPA (10mg/kg; n=10) or vehicle (n=10) for 14 days. Disease activity was assessed by measurement of mouse weight, colonic weight and length, histological score, cytokine levels in colonic homogenate and lipocalin-2 levels in stool. To examine for possible direct effects of EMPA, colonic explants from wild-type (n=8) and IL-10-/- (n=8) mice were incubated with increasing doses of EMPA (0.1–5 µM) ± LPS (10µg/ml) for 2 hours and tissue levels of IL-1β and TNFα protein measured by ELISA. Results After 14 days EMPA treated IL-10-/- mice had a significant improvement in colonic inflammation as evidenced by decreased colonic weight to length ratio (p=0.019), decreased fecal lipocalin-2 (p=0.03), as well as decreased enterocyte injury (p=0.01), decreased lamina propria neutrophils (p=0.01) and decreased total histological score (p=0.006). EMPA treated mice also maintained their weight over the 14 days while untreated mice continued to lose weight (p=0.04). There were no significant differences in colonic homogenate levels of TNFα, IL-1β, or IL-6 or in blood glucose levels between EMPA-treated mice and controls. In addition, EMPA did not suppress levels of basal or LPS-induced TNFα and IL-1β in colonic explants from either wild-type or IL-10-/- mice suggesting that the beneficial effects in IL-10-/- mice were not due to direct effects of EMPA on colonic TNFα or IL-1β cytokine levels. Conclusions EMPA treatment dramatically improved histologic and fecal inflammatory markers and maintained body weight in adult IL-10-/- mice with established colitis. These findings suggest further investigations into the effects of EMPA in treating gut inflammation are warranted. Funding Agencies CAG, CIHR

Haloperidol and Risperidone at high concentrations activate an in vitro inflammatory response of RAW 264.7 macrophage cells by induction of apoptosis and modification of cytokine levels

2015 ◽  
Vol 233 (9) ◽  
pp. 1715-1723 ◽  
Author(s):  
Ivo Emílio da Cruz Jung ◽  
Alencar Kolinski Machado ◽  
Ivana Beatrice Mânica da Cruz ◽  
Fernanda Barbisan ◽  
Verônica Farina Azzolin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Raw 264.7 ◽  
Macrophage Cells ◽  
Raw 264.7 Macrophage ◽  
Cytokine Levels ◽  
Raw 264.7 Macrophage Cells ◽  
Induction Of Apoptosis ◽  
High Concentrations

Chemoattractants: Their essentiality and efficacy in shrimp aquaculture

2021 ◽  
Vol 68 (1) ◽  
Author(s):  
R. Jannathulla ◽  
O. Sravanthi ◽  
H. Imran Khan ◽  
H. Syed Moomeen ◽  
A. Gomathi ◽  
...  
Keyword(s):  
Chemical Compounds ◽  
Nutritional Composition ◽  
Present Review ◽  
Shrimp Aquaculture ◽  
Aquatic Species ◽  
Beneficial Effects ◽  
Shrimp Feed ◽  
High Concentrations ◽  
Plant Sources ◽  
Selection Of

Aquaculture serves as a sustainable source of good quality wholesome food and major input is feed. In recent years, considerable quantities of plant sources have been attempted for inclusion in shrimp feed, due to high demand and high cost of fishmeal. Plant-based ingredients are in general poor in attractability and palatability to aquatic species compared to marine sources. It is desirable to develop an economical and nutritious feed that is attractive and palatable for ensuring reduction of feed wastage. Chemoattractants nowadays are unavoidable in commercial shrimp feeds and are included either individually or in combination. The present review revealed that the various marine sources, in particular krill meal would be more effective for aquatic species, compared to those derived from vegetable origin and chemical compounds. In addition to acting as a feed attractant, marine sources serve as a potential fishmeal substitute due to their rich nutritional composition. However, certain biogenic amines present in these marine-based ingredients need to be examined before their use, since these amines when present in high concentrations reduces feed intake by producing undesirable odour. Use of a combination of chemoattractants would give a better effect, rather than using them individually and compounds from plant origin have limited beneficial effects. The present review concludes that incorporation of chemoattractants would be beneficial in formulation of enriched and economical feeds with better attractability and palatability. The selection of suitable attractant and their supplementation at correct proportion is significantly more important to avoid undesirable effects in cultured shrimp. Further field-based research is needed to predict the actual effects of chemoattractants on farmed shrimp and to provide a sustainable base for the expansion of shrimp aquaculture sector, by reducing feed wastage.

scholarly journals High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn- IgG complexes

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 184-193 ◽  
Author(s):  
HU Lutz ◽  
P Stammler ◽  
E Jelezarova ◽  
M Nater ◽  
PJ Spath
Keyword(s):  
Inflammatory Diseases ◽  
Factor H ◽  
Human Igg ◽  
Partial Protection ◽  
Beneficial Effects ◽  
High Concentrations ◽  
High Doses ◽  
Immune Aggregates

Abstract Intravenously applied human IgG has beneficial effects in treating inflammatory diseases, presumably because it has a complement attenuating role. This role of IgG was studied in vitro by following C3 activation and inactivation in sera that were supplemented with exogenous human IgG and incubated with immune aggregates. IgG added at 2 to 10 mg/mL stimulated the physiologic inactivation of C3b-containing complexes twofold to threefold in 20% sera. This, in turn, lowered the overall C3 activation by 28%, as new C3 convertases primarily assembled on C3b-containing complexes. Exogenous IgG (5 mg/mL) also stimulated inactivation of purified C3b2-IgG complexes, whereby their half-life dropped from 3–4 to 1.5 minutes in 20% serum. IgG appeared to act like a modulator of factor H and I because it did not stimulate inactivation of C3b-containing complexes in factor I-deficient serum. Thus, the known partial protection of C3bn-IgG complexes from inactivation by factor H and I was downregulated by high concentrations of IgG. The ability of high doses of IgG to stimulate complement inactivation is a novel regulatory role of IgG. This may be one of the molecular principles for its therapeutic efficacy in treating complement-mediated inflammations.

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