Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei

Gamage, Akshamal M; Lee, Kok-Onn; Gan, Yunn‐Hwen

doi:10.1016/j.micinf.2014.07.007

Cited by 8 publications

(11 citation statements)

References 43 publications

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“…Additionally, the levels of total GSH did not increase due to NAC supplementation among the T2DM subjects either (data not shown). Similarly, a preceding study reported that after oral NAC supplementation, the levels of in vivo GSH did not improve among T2DM patients ( 75 ). We suspect that this is due to the fact that T2DM individuals have attenuated levels of GSH synthesizing enzymes, and therefore despite elevating NAC (the GSH precursor), they are not capable of upregulating the extent of GSH produced ( 54 ).…”

Section: Discussionmentioning

confidence: 67%

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis

et al. 2018

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Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.

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Section: Discussionmentioning

confidence: 67%

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis

et al. 2018

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“…Antioxidant drugs, such as N ‐acetyl‐ l ‐cysteine (NAC) and deferoxamine (DFX), have shown anti‐inflammatory and antioxidant properties by reducing cytokines and oxidative stress, respectively (De Flora et al , 1991; ). Moreover, both NAC and DFX exerted beneficial effects on both diabetes and depression .…”

Section: Introductionmentioning

confidence: 99%

Antioxidant treatment ameliorates experimental diabetes‐induced depressive‐like behaviour and reduces oxidative stress in brain and pancreas

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Santos

Abelaira

et al. 2015

Diabetes Metabolism Res

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Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes.

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“…PBMCs, CD14 + monocytes, or NK cells were isolated as described previously (11), and resuspended in RPMI 1640 + 10% FBS at the typical densities of 2, 0.25, and 0.25 million cells per ml per well respectively. Overnight bacterial cultures were added to cells at the relevant multiplicity of infection (MOI) assuming that 1 OD 600 of bacterial culture has ∼1 3 10 9 CFU per ml.…”

Section: Cell Infectionmentioning

confidence: 99%

“…We have previously shown that Type 2 diabetic patients, who are at increased risk for developing acute melioidosis and severe disease (9), showed defective IL-12 and IFN-g production in response to B. pseudomallei infection (10). The production of IL-12 from infected monocytes induced IFN-g secretion from NK cells, and this in turn activated the microbicidal activity of monocytes to control intracellular bacterial numbers (11). This defective IL-12/ IFN-g axis in diabetic patients was linked to a lower glutathione (GSH) ratio.…”

mentioning

confidence: 99%

“…This defective IL-12/ IFN-g axis in diabetic patients was linked to a lower glutathione (GSH) ratio. Although ex vivo addition of free GSH could boost IL-12 production from monocytes upon infection (10), oral supplementation with N-acetylcysteine (a GSH prodrug) in diabetic patients could not reverse the cytokine defect when diabetic peripheral blood mononuclear cells (PBMCs) were infected ex vivo (11). This prompted us to examine whether other molecules have the potential to increase IL-12 production independently of the GSH ratio, during B. pseudomallei infection.…”

mentioning

confidence: 99%

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Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

Gamage

Lee

Gan

2017

The Journal of Immunology

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The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-γ, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with and HMBA treatment was also associated with better intracellular bacterial control. HMBA significantly improved IL-12p70 production from CD14 monocytes during infection partly via the induction of type I IFN in these cells, which primed an increased transcription of the p35 subunit of IL-12p70 during infection. HMBA also increased early type I IFN transcription in human monocytic and epithelial cell lines, but this was surprisingly independent of its previously reported effects on positive transcription elongation factor b and HMBA inducible protein-1. Instead, the effect of HMBA was downstream of a calcium influx, and required the pattern recognition receptor and adaptor STING but not cGAS. Our work therefore links the STING-IRF3 axis to enhanced IL-12 production and intracellular bacterial control in primary monocytes. This raises the possibility that HMBA or related small molecules may be explored as therapeutic adjuvants to improve disease outcomes during intracellular bacterial infections.

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Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei

Cited by 8 publications

References 43 publications

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis

Antioxidant treatment ameliorates experimental diabetes‐induced depressive‐like behaviour and reduces oxidative stress in brain and pancreas

Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

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