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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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Cashew apple juice supplementation enhances leukocyte count by reducing oxidative stress after high-intensity exercise in trained and untrained men.
Prasertsri, P, Roengrit, T, Kanpetta, Y, Tong-Un, T, Muchimapura, S, Wattanathorn, J, Leelayuwat, N
Journal of the International Society of Sports Nutrition. 2019;16(1):31
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High-intensity aerobic training has been shown to suppress leukocyte counts in moderately fit athletes. The aim of this study to explore possible advantageous effects of cashew apple juice (CAJ) supplementation, and, if present, to identify the possible mechanisms underlying those effects. The study is a double-blind randomised cross-over design with two treatment arms: CAJ supplementation and placebo. Ten moderately (endurance) trained and untrained men were randomized to one of the two groups for four weeks, with a four-week wash out period. Results showed that CAJ supplementation for four weeks increased leukocyte (a type of blood cell) counts, while simultaneously decreasing oxidative stress, following an acute bout of high-intensity exercise in trained men. Furthermore, the CAJ supplementation increased neutrophil (a type of white blood cell) counts while simultaneously reducing oxidative stress and stress hormone concentrations in untrained men. The antioxidant effects following exercise were observed in both endurance-trained and untrained men. Authors conclude that CAJ supplementation is beneficial to men, both in resting states and in response to an acute bout of high-intensity aerobic exercise.
Abstract
BACKGROUND Cashew apple juice (CAJ) was shown to improve immunological mechanisms by regulating a balance between reactive oxygen species and antioxidant concentrations. However, no study exploring the effects of the CAJ and training status on the immune system and oxidative stress induced by exercise. Therefore, we investigated the effects of CAJ supplementation primarily on leukocyte counts and secondary on oxidative stress and cortisol changes after high-intensity exercise in trained and untrained men. METHODS Ten moderately (endurance) trained (Age = 21.5 ± 0.97 yr., VO2max = 45.6 ± 4.12 mL/kgBM/min) and ten sedentary men (Age = 20.4 ± 2.72 yr., VO2peak = 32.2 ± 7.26 mL/kgBM/min) were randomized to ingest either daily CAJ or a placebo at 3.5 mL/kgBM/day for 4 weeks, with a four-week washout period. Before and after each period, they performed 20-min, high-intensity cycling (85% VO2max), with blood samples collected immediately preceding and the following exercise. Samples were analyzed to determine leukocyte counts, malondialdehyde, 8-isoprostane, and cortisol concentrations. A repeated measures analysis of variance was used to examine the effects of supplement and training status over time with an alpha level of 0.05. RESULTS There was no interaction between supplement and training status on those variables before and after exercise. However, CAJ raised resting neutrophil counts and exercise-induced leukocyte counts in the trained group (all p < 0.05). Besides, CAJ significantly reduced plasma malondialdehyde concentrations at rest and after exercise and reduced the post-exercise plasma 8-isoprostane concentration in both groups of subjects (p < 0.05). Moreover, CAJ reduced plasma cortisol after exercise in the untrained subjects. CONCLUSIONS We suggest that 4-week CAJ supplementation can enhance exercise-induced leukocyte and resting neutrophil counts in trained men. The possible mechanism is a reduction in oxidative stress. However, the supplementation did not change the immune responses of untrained men, but it did reduce stress hormone concentrations. TRIAL REGISTRATION NUMBER TCTR20181127002 Registered 26 November 2018 "retrospectively registered".
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The study evaluating the effect of probiotic supplementation on the mental status, inflammation, and intestinal barrier in major depressive disorder patients using gluten-free or gluten-containing diet (SANGUT study): a 12-week, randomized, double-blind, and placebo-controlled clinical study protocol.
Karakula-Juchnowicz, H, Rog, J, Juchnowicz, D, Łoniewski, I, Skonieczna-Żydecka, K, Krukow, P, Futyma-Jedrzejewska, M, Kaczmarczyk, M
Nutrition journal. 2019;18(1):50
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Major depressive disorder (MDD) has historically been recognised as a brain disease, however more recently it is being recognised as a whole-body disorder. The immune system and the gut microbiota have been implicated in MDD with particular focus on the gut wall integrity and the resultant immune reaction and its influence on the brain. Gluten may incite an immune reaction in certain individuals and a gluten free diet may be of benefit to symptoms of depression in those who have gluten-related disorders. This randomised prospective control trial of 120 patients with MDD aims to determine the effect of a gluten free diet and probiotic supplementation in symptom management over 12 weeks. As this was a prospective study, no results were achieved. However, the study does indicate that randomised control trials on the effect of diet in MDD are advancing and there may be scientifically proven avenues to support standard therapies.
Abstract
BACKGROUND Current treatment of major depressive disorder (MDD) often does not achieve full remission of symptoms. Therefore, new forms of treatment and/or adjunct therapy are needed. Evidence has confirmed the modulation of the gut-brain-microbiota axis as a promising approach in MDD patients. The overall purpose of the SANGUT study-a 12-week, randomized, double-blind, and placebo-controlled Study Evaluating the Effect of Probiotic Supplementation on the Mental Status, Inflammation, and Intestinal Barrier in Major Depressive Disorder Patients Using Gluten-free or Gluten-containing Diet - is to determine the effect of interventions focused on the gut-brain-microbiota axis in a group of MDD patients. METHODS A total of 120 outpatients will be equally allocated into one of four groups: (1) probiotic supplementation+gluten-free diet group (PRO-GFD), (2) placebo supplementation+ gluten-free diet group (PLA-GFD), (3) probiotic supplementation+ gluten containing diet group (PRO-GD), and (4) placebo supplementation+gluten containing diet group (PLA-GD). PRO groups will receive a mixture of psychobiotics (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175), and GFD groups will follow a gluten-free diet. The intervention will last 12 weeks. The primary outcome measure is change in wellbeing, whereas the secondary outcome measures include physiological parameters. DISCUSSION Microbiota and its metabolites have the potential to influence CNS function. Probiotics may restore the eubiosis within the gut while a gluten-free diet, via changes in the microbiota profile and modulation of intestinal permeability, may alter the activity of microbiota-gut-brain axis previously found to be associated with the pathophysiology of depression. It is also noteworthy that microbiota being able to digest gluten may play a role in formation of peptides with different immunogenic capacities. Thus, the combination of a gluten-free diet and probiotic supplementation may inhibit the immune-inflammatory cascade in MDD course and improve both psychiatric and gut barrier-associated traits. TRIAL REGISTRATION NCT03877393 .