Increased Mitochondrial Electron Transport Chain Activity at Complex I Is Regulated by<i>N</i>-Acetylcysteine in Lymphocytes of Patients with Systemic Lupus Erythematosus

Doherty, Edward; Oaks, Zachary; Perl, András

doi:10.1089/ars.2013.5702

Cited by 84 publications

(56 citation statements)

References 30 publications

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“…Studies have indicated that NAC can decrease the oxygen consumption in mitochondria (21) and block mTOR, a regulator of oxygen consumption and oxidative stress in mitochondria (22), which is consistent with the present finding that NAC increased the GSH and decreased the 8-iso-PGF2α levels in LN. Accordingly, after 12 weeks of treatment, the relative indexes, such as WBC, 24-h urine protein and ESR, were largely improved, and the SLEDAI was notably decreased, reflecting a satisfactory therapeutic outcome.…”

Section: Discussionsupporting

confidence: 93%

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases

Gao

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The oxidative-antioxidative status is closely associated with the progression of systemic lupus erythematosus (SLE), and oxidative stress is customarily found in patients with SLE. N-acetylcysteine (NAC), a typical antioxidant, is reliable and often applied for clinical treatment. Lupus nephritis (LN) is a kidney disorder associated with SLE, but the treatment of LN with antioxidants is rarely documented. The present report describes two cases of early-stage LN that were orally treated with 1,200 mg NAC in addition to the standard therapy with hydroxychloroquine and calcitriol. Following the NAC administration, the glutathione level largely increased while the level of the lipid peroxidation biomarker 8-iso-prostaglandin F2α declined in both cases. In addition, the routine blood counts, 24-h urine protein, erythrocyte sedimentation rate and the SLE disease activity index were markedly improved. In conclusion, the present report of two cases has shown that NAC, as an antioxidant, may exert a beneficial effect to modulate the oxidative status in LN; however, the underlying mechanisms require further investigation. IntroductionSystemic lupus erythematosus (SLE), a chronic and multisystem autoimmune disorder that is characterized by dysregulated immune responses and production of pathogenic autoantibodies by immune cells such as B-cells, T-cells and dendritic cells (1). The clinical presentations of SLE include rash, oral ulcers, fatigue and arthralgias, and the course of the disease is unpredictable, with periods of flares alternating with remission (1). The pathogenesis of SLE remains unclear, and autoantibodies, proinflammatory and anti-inflammatory cytokines, lymphocyte subset abnormalities as well as genetic predispositions may contribute to the development of SLE (2). The disease occurs more often in women, with an incidence about nine times higher compared to men, and is also more common in non-Caucasian descent (1). SLE can affect the majority of organs and tissues such as skin, joints, lungs, blood vessels and kidneys. Lupus nephritis (LN) is a sever consequence of SLE, and ~ 40-70% of patients with SLE would develop LN (3).At present, LN is primarily treated with corticosteroids and immunosuppressive drugs, but is often associated with high morbidity and suboptimal outcomes (4). As an inflammation of the kidney caused by systemic lupus erythematosus (SLE), LN has been documented to be closely associated with the imbalance between oxidative and antioxidative activities during the pathogenesis of LN (5,6). The few studies that have investigated the use of antioxidants in the treatment of LN have resulted in a satisfactory outcome (7,8). N-acetylcysteine (NAC) is a typical antioxidant that is often used during clinical treatments (9). It is believed that NAC primarily acts as a glutathione precursor to minimize the hepatic risk caused by paracetamol poisoning (10). The present report describes two cases of early-stage LN that were treated with NAC. Case reportTwo female patients were diagnosed with ...

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Section: Discussionsupporting

confidence: 93%

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases

Gao

et al. 2015

Experimental and Therapeutic Medicine

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“…However, NAC treatment inhibited the activity of Complex I but not Complex IV. This could be because NAC acts as a redox sensor by inhibiting the Complex I activity and limiting the oxygen and NADH utilization, thus reducing oxidative stress [52]. Complex I may also be inhibited by excess GSH through glutathionylation [53] since NAC treatment results in an increase in GSH levels.…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Alnahdi¹,

John²,

Raza³

2018

Cell Physiol Biochem

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Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

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“…9 The decreased activity of Complex I in our study may be related to the reverse electron transfer (RET), which may influence the mitochondria to produce elevated levels of ROS. Doherty et al (2014) reported the elevated levels in the complex I activity in peripheral blood lymphocytes of SLE patients measured by the levels of oxygen consumption. 34 It is in contrast with our study, however, as we studied the activity of enzyme complexes themselves, from isolated mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Doherty et al (2014) reported the elevated levels in the complex I activity in peripheral blood lymphocytes of SLE patients measured by the levels of oxygen consumption. 34 It is in contrast with our study, however, as we studied the activity of enzyme complexes themselves, from isolated mitochondria. The population of cells we studied involved monocytes too, and it is this cell that is known to fight using its armory of ROS.…”

Section: Discussionmentioning

confidence: 99%

Role of altered mitochondria functions in the pathogenesis of systemic lupus erythematosus

Leishangthem

Sharma

Bhatnagar

2015

Lupus

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Mitochondria, main producers of reactive-oxygen species (ROS), were studied to examine their role in the pathogenesis of systemic lupus erythematosus (SLE). PBMCs and mitochondria were isolated from SLE patients and healthy volunteers for various parameters. Mitochondrial ROS, swelling, hyperpolarization and levels of cytochrome c, caspase3 in the cells were assessed by flow cytometry. ROS was significantly increased in SLE patients (SLE vs controls: 1.83 ± 1.03 vs 1.10 ± 0.35; p < 0.0001). Depolarized state of mitochondria was greater in patients (SLE vs controls: 7.10 ± 5.50% vs 2.5 ± 1.8%; p < 0.05). Mitochondria swelling was found to be significantly altered in patients (SLE vs controls: 112.65 ± 36.56 vs 60.49 ± 20.69; p < 0.001). Expression of cytochrome c and caspase 3 (SLE vs controls: 1.37 ± 0.37% vs 1.01 ± 0.03%; 1.57 ± 0.46% vs 1.06 ± 0.07%; p < 0.05) respectively was found to be significantly increased in SLE. Further, the enzymatic activity of mitochondrial complex was assessed in isolated mitochondria. A significant decrease in activity of Complex I (SLE vs controls: 11.79 ± 3.18 vs 15.10 ± 6.38 nmol NADH oxidized/min/mg protein, p < 0.05); Complex IV (SLE vs control: 9.41 ± 5.16 vs 13.56 ± 5.92 nmol cytochrome c oxidized/min/mg protein, p < 0.05) and Complex V (SLE vs controls: 4.85 ± 1.39 vs 6.17 ± 2.02 nmol ATP hydrolyzed/min/mg protein, p < 0.05) was found in SLE patients in comparison to healthy controls. However, Complex II did not show significant variation in either group (SLE vs controls: 42.2 ± 28.6 vs 61.71 ± 42.3 nmol succinate oxidized/min/mg protein; ns). The decrease in enzyme activities of mitochondrial Complexes I, IV and V on one hand and ROS, hyperpolarization and apoptosis on the other points toward a possible role of mitochondria in the pathogenesis of lupus.

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Increased Mitochondrial Electron Transport Chain Activity at Complex I Is Regulated byN-Acetylcysteine in Lymphocytes of Patients with Systemic Lupus Erythematosus

Cited by 84 publications

References 30 publications

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases

Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases

Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Role of altered mitochondria functions in the pathogenesis of systemic lupus erythematosus

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