scholarly journals Immunomodulatory Properties of Polyphenol-Rich Sugarcane Extract on Human Monocytes

Biologics ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 211-221
Author(s):  
Jack Feehan ◽  
Monica D. Prakash ◽  
Lily Stojanovska ◽  
Matthew Roland Flavel ◽  
Barry Kitchen ◽  
...  
Keyword(s):  
Human Monocyte ◽  
Immunomodulatory Effect ◽  
Plant Polyphenols ◽  
Future Studies ◽  
Animal Models Of Disease ◽  
Beneficial Effects ◽  
Immunomodulatory Properties ◽  
High Concentrations ◽  
Models Of Disease

As inflammatory lifestyle factors become more prevalent and as the population ages, the management of inflammation will become increasingly relevant. Plant polyphenols are powerful antioxidants that are known to have beneficial effects in a number of diseases with an inflammatory or oxidative component, such as malignancy, cardiovascular disease and arthritis. Polyphenol-rich sugarcane extract (PRSE) is a novel preparation with high concentrations of polyphenolic antioxidants, with some evidence to show benefits in health, but there is limited research investigating its effects on immunomodulation. This study determined the effects of PRSE on human monocyte cells in vitro. We show that PRSE has an immunomodulatory effect in U937 human monocyte cells, altering the expression of cellular surface markers, with an increased expression of CD16 and CD11b, as well as small changes in CD40, CD80, CD80, CD206 and MHCI. It also modulates the profile of secreted cytokines, increasing IL-1β, TNFα, IL-6, IL-8, IL-4 and IL-10. These changes are consistent with the advanced differentiation of the monocyte, as well as the switch from the M1 to M2 phenotype in macrophages. We also demonstrate that this effect is likely to be independent of the NF-κB signalling pathway, suggesting that other mechanisms drive this effect. PRSE exerts an immunomodulatory effect on U937 monocytes in vitro, potentially facilitating the conversion from inflammation to healing. Future studies should identify specific mechanisms underlying the changes and evaluate their effectiveness in animal models of disease.

Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

2019 ◽  
Vol 26 (27) ◽  
pp. 5207-5229 ◽  
Author(s):  
Y.V. Madhavi ◽  
Nikhil Gaikwad ◽  
Veera Ganesh Yerra ◽  
Anil Kumar Kalvala ◽  
Srinivas Nanduri ◽  
...  
Keyword(s):  
Diabetic Complications ◽  
Energy Homeostasis ◽  
Cardiovascular Complications ◽  
Living System ◽  
Animal Models Of Disease ◽  
Beneficial Effects ◽  
Inflammatory Processes ◽  
Energy Sensing ◽  
Healthy Functioning ◽  
Models Of Disease

Adenosine 5′-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

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.

scholarly journals Shiga Toxin Subtypes Display Dramatic Differences in Potency

2011 ◽  
Vol 79 (3) ◽  
pp. 1329-1337 ◽  
Author(s):  
Cynthia A. Fuller ◽  
Christine A. Pellino ◽  
Michael J. Flagler ◽  
Jane E. Strasser ◽  
Alison A. Weiss
Keyword(s):  
Shiga Toxin ◽  
Vero Cells ◽  
Epidemiologic Studies ◽  
Systemic Complications ◽  
Animal Models Of Disease ◽  
Uremic Syndrome ◽  
Models Of Disease ◽  
Relative Potencies

ABSTRACTPurified Shiga toxin (Stx) alone is capable of producing systemic complications, including hemolytic-uremic syndrome (HUS), in animal models of disease. Stx includes two major antigenic forms (Stx1 and Stx2), with minor variants of Stx2 (Stx2a to -h). Stx2a is more potent than Stx1. Epidemiologic studies suggest that Stx2 subtypes also differ in potency, but these differences have not been well documented for purified toxin. The relative potencies of five purified Stx2 subtypes, Stx2a, Stx2b, Stx2c, Stx2d, and activated (elastase-cleaved) Stx2d, were studiedin vitroby examining protein synthesis inhibition using Vero monkey kidney cells and inhibition of metabolic activity (reduction of resazurin to fluorescent resorufin) using primary human renal proximal tubule epithelial cells (RPTECs). In both RPTECs and Vero cells, Stx2a, Stx2d, and elastase-cleaved Stx2d were at least 25 times more potent than Stx2b and Stx2c.In vivopotency in mice was also assessed. Stx2b and Stx2c had potencies similar to that of Stx1, while Stx2a, Stx2d, and elastase-cleaved Stx2d were 40 to 400 times more potent than Stx1.

scholarly journals Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

2008 ◽  
Vol 76 (6) ◽  
pp. 2333-2340 ◽  
Author(s):  
Laura E. Via ◽  
P. Ling Lin ◽  
Sonja M. Ray ◽  
Jose Carrillo ◽  
Shannon Sedberry Allen ◽  
...  
Keyword(s):  
Animal Models ◽  
Guinea Pig ◽  
Nonhuman Primate ◽  
Culture Conditions ◽  
Low Oxygen ◽  
Animal Models Of Disease ◽  
Hypoxic Conditions ◽  
Models Of Disease ◽  
Pulmonary Granulomas

ABSTRACT Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O2. Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 ± 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.

scholarly journals A Novel Small Molecule Inhibits Intrahepatocellular Accumulation of Z-Variant Alpha 1-Antitrypsin In Vitro and In Vivo

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1586 ◽  
Author(s):  
Xiaojuan Zhang ◽  
Kien Pham ◽  
Danmeng Li ◽  
Ryan J. Schutte ◽  
David Hernandez Gonzalo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Cell Model ◽  
Curative Therapy ◽  
Animal Models Of Disease ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Models Of Disease

Alpha 1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and is associated with early-onset chronic liver disease in adults. AATD associated liver injury is caused by hepatotoxic retention of polymerized mutant alpha 1-antitrypsin molecules within the endoplasmic reticulum. Currently, there is no curative therapy for AATD. In this study, we selected small molecules with the potential to bind mutant alpha 1-antitrypsin (Z-variant) to inhibit its accumulation in hepatocytes. We used molecular docking to select candidate compounds that were validated in cell and animal models of disease. A crystal structure of polymerized alpha 1-antitrypsin molecule was used as the basis for docking 139,735 compounds. Effects of the top scoring compounds were investigated in a cell model that stably expresses Z-variant alpha 1-antitrypsin and in PiZ mice expressing Z-variant human alpha 1-antitrypsin (Z-hAAT), encoded by SERPINA1*E342K. 4′,′5-(Methylenedioxy)-2-nitrocinnamic acid was predicted to bind cleaved alpha 1-antitrypsin at the polymerization interface, and observed to co-localize with Z-hAAT, increase Z-hAAT degradation, inhibit intracellular accumulation of Z-hAAT, and alleviate liver fibrosis.

Dose-dependent effects of gonadotropin on oocyte developmental competence and apoptosis

2011 ◽  
Vol 23 (8) ◽  
pp. 990 ◽  
Author(s):  
Shan Liu ◽  
Huai L. Feng ◽  
Dennis Marchesi ◽  
Zi-Jiang Chen ◽  
Avner Hershlag
Keyword(s):  
Embryo Development ◽  
Assisted Reproductive Technologies ◽  
Cumulus Cells ◽  
Reproductive Technologies ◽  
Developmental Competence ◽  
Beneficial Effects ◽  
Nuclear Maturation ◽  
High Concentrations ◽  
Vitro Development

The aim of the present study was to evaluate the effect of gonadotropins (Gn) on oocyte maturation, developmental competence and apoptosis in an animal model. Bovine cumulus–oocyte complexes (COCs) were matured for 24 h in media supplemented with varying concentrations of Bravelle (B), B + Menopur (B + M) or B + Repronex (B + R) (Ferring Pharmaceuticals, Parsiappany, NJ, USA). Then, nuclear maturation, embryo development, and apoptosis in cumulus cells and oocytes were evaluated. Low to moderate Gn concentrations (75–7500 mIU mL–1) effectively improved nuclear maturation and in vitro development. Higher concentrations of Gn (75 000 mIU mL–1) did not have any added beneficial effects and nuclear maturation and blastocyst rates in the presence of these concentrations were comparable to control (P > 0.05). Most COCs showed slight apoptosis when exposed to 75, 750 and 7500 mIU mL–1 Gn; however, when the concentration was increased to 75 000 mIU mL–1, the proportion of moderately apoptotic COCs increased. In conclusion, extremely high concentrations of Gn have detrimental effects on oocyte nuclear maturation and embryo development and increase apoptosis in cumulus cells, suggesting the importance of judicious use of Gn in assisted reproductive technologies (ART).

High insulin concentrations promote the in vitro growth and viability of canine preantral follicles

2013 ◽  
Vol 25 (6) ◽  
pp. 927 ◽  
Author(s):  
Michelle K. B. Serafim ◽  
Gerlane M. Silva ◽  
Ana B. G. Duarte ◽  
V. R. Araújo ◽  
T. F. P. Silva ◽  
...  
Keyword(s):  
Culture Medium ◽  
Formation Rate ◽  
Minimum Essential Medium ◽  
Preantral Follicles ◽  
Beneficial Effects ◽  
Culture Viability ◽  
High Insulin ◽  
High Concentrations ◽  
High Insulin Concentration

To determine whether the effects of different concentrations of insulin on the development of canine preantral follicles in vitro were associated or not with FSH, secondary follicles were isolated and cultured. In Experiment 1, follicles were cultured in the following media: modified minimum essential medium (CtrlMEM) alone; CtrlMEM plus 5 ng mL–1 insulin (Ins5ng); CtrlMEM plus 10 ng mL–1 insulin (Ins10ng); and CtrlMEM plus 10 μg mL–1 insulin. In Experiment 2, follicles were cultured in the same media but in the presence of sequential FSH (i.e. CtrlFSH, Ins5ngF, Ins10ngF and 10μgF, respectively). Increasing concentrations of FSH (100, 500 and 1000 ng mL–1) were added sequentially to the culture medium on Days 0, 6 and 12 of culture. Viability were assessed at the end of culture and follicular diameter and the antrum formation rate at four time points (Days 0, 6, 12 and 18). In Experiment 1, the high insulin concentration significantly increased follicular viability (P < 0.05). In contrast, in Experiment 2, viability was not affected by the inclusion of insulin. In addition, viability was significantly better in follicles cultured in CtrlFSH (P < 0.05). The diameter of follicles in the high-insulin group in Experiment 1 and high-insulin plus FSH group in Experiment 2 was superior to other groups tested. In experiment 2, the Ins10μg and Ins10μgF groups exhibited significantly higher antrum formation rates than the other groups. In conclusion, in the absence of FSH, high concentrations of insulin have beneficial effects on follicular viability. However, to promote the growth of canine preantral follicles in vitro, it is recommended that a combination of insulin and FSH be added to the medium.

scholarly journals Cardiovascular benefits of lycopene: fantasy or reality?

2016 ◽  
Vol 76 (2) ◽  
pp. 122-129 ◽  
Author(s):  
Frank Thies ◽  
Lynsey M. Mills ◽  
Susan Moir ◽  
Lindsey F. Masson
Keyword(s):  
Inflammatory Markers ◽  
Dietary Factors ◽  
Cvd Risk ◽  
Cardiovascular Protection ◽  
Beneficial Effects ◽  
Reactive Protein ◽  
Hdl Functionality ◽  
High Concentrations ◽  
Intervention Trials

Epidemiological evidence indicates that high consumption of tomatoes and tomato-based products reduces the risk of chronic diseases such as CVD and cancer. Such potential benefits are often ascribed to high concentrations of lycopene present in tomato products. Mainly from the results of in vitro studies, potential biological mechanisms by which carotenoids could protect against heart disease and cancer have been suggested. These include cholesterol reduction, inhibition of oxidation processes, modulation of inflammatory markers, enhanced intercellular communication, inhibition of tumourigenesis and induction of apoptosis, metabolism to retinoids and antiangiogenic effects. However, with regard to CVD, results from intervention studies gave mixed results. Over fifty human intervention trials with lycopene supplements or tomato-based products have been conducted to date, the majority being underpowered. Many showed some beneficial effects but mostly on non-established cardiovascular risk markers such as lipid peroxidation, DNA oxidative damage, platelet activation and inflammatory markers. Only a few studies showed improvement in lipid profiles, C reactive protein and blood pressure. However, recent findings indicate that lycopene could exert cardiovascular protection by lowering HDL-associated inflammation, as well as by modulating HDL functionality towards an antiatherogenic phenotype. Furthermore, in vitro studies indicate that lycopene could modulate T lymphocyte activity, which would also inhibit atherogenic processes and confer cardiovascular protection. These findings also suggest that HDL functionality deserves further consideration as a potential early marker for CVD risk, modifiable by dietary factors such as lycopene.

Validation of Di-5-HT-Gd-DTPA, an Enzyme-Specific MR Contrast Agent for Myeloperoxidase, in the Rabbit Elastase Model of Cerebrovascular Aneurysm

2009 ◽  
Author(s):  
Michael J. DeLeo ◽  
Matthew J. Gounis ◽  
Ajay K. Wakhloo ◽  
Alexei A. Bogdanov
Keyword(s):  
Contrast Agent ◽  
Rabbit Model ◽  
Zealand White Rabbit ◽  
Animal Models Of Disease ◽  
Diagnostic Potential ◽  
Molecular Imaging Probes ◽  
Imaging Probes ◽  
Models Of Disease ◽  
Active Inflammation

Characterization of molecular imaging probes in multiple animal models of disease is essential to increase their diagnostic potential. For example, we recently demonstrated visualization of active inflammation in a rabbit model saccular aneurysm using clinical field strength MRI and the paramagnetic MR contrast agent di-5-HT-GdDTPA, which has been shown in vitro to be sensitive and specific for the enzyme myeloperoxidase (MPO). While the use of transgenic mice (MPO−/−) has demonstrated specificity of di-5-HT-GdDTPA for MPO in a model of myocardial infarction [1], MPO-deficient rabbits are not available. Therefore, in this study, we sought to validate di-5-HT-GdDTPA MPO specificity in the New Zealand white rabbit by comparing serial enhancement ratios of di-5-HT-GdDTPA to a structurally similar MR contrast agent, di-Tyr-GdDTPA, which is activated by peroxidases but not by MPO. Structural diagrams of the synthesis of the two agents are demonstrated in Figure 1 [2].

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