Effects of N-acetylcysteine supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in rheumatoid arthritis patients: a randomized double-blind placebo-controlled trial

Esalatmanesh, Kamal; Jamali, Alireza; Esalatmanesh, Roozbeh; Soleimani, Zahra; Khabbazi, Alireza; Mahdavi, Aida Malek

doi:10.1007/s00726-022-03134-8

Cited by 14 publications

(24 citation statements)

References 53 publications

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“…N-acetylcysteine (NAC) is one of the most studied antioxidant agents for therapeutic treatment. A recent clinical study showed that NAC did not improve RA disease activity [ 189 ]. NRF2 activators are being investigated as potential agents for increasing antioxidant capacity and alleviating disease.…”

Section: Targeted Ros Therapy For Ramentioning

confidence: 99%

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

et al. 2022

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Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading to synovitis and bone and cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents of cellular components or they act as signaling molecules in the immune system. During the development of RA, a hypoxic and inflammatory situation in the synovium maintains ROS generation, which can be sustained by increased DNA damage and malfunctioning mitochondria in a feedback loop. Oxidative stress caused by abundant ROS production has also been shown to be associated with synovitis in RA. The goal of this review is to examine the functions of ROS and related molecular mechanisms in diverse cells in the synovial microenvironment of RA. The strategies relying on regulating ROS to treat RA are also reviewed.

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Section: Targeted Ros Therapy For Ramentioning

confidence: 99%

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

et al. 2022

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“…This cytokine triggers local inflammation and, in fact, induces synovial macrophages to generate proinflammatory cytokines, including IL-6 and IL-1β [53]. The latter, in turn, induces osteoclastogenesis by acting directly on osteoclast precursor cells, responsible for bone erosion [52,54]. Additionally, TNF-α has been found to mediate a series of immune effector functions that induce inflammatory responses and pannus formation, supporting the cartilage destruction and bone erosion of RA [55].…”

Section: Discussionmentioning

confidence: 99%

Toxic Effects of Endocrine Disruptor Exposure on Collagen-Induced Arthritis

et al. 2022

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Endocrine disruptors (EDs) are chemical substances capable of affecting endocrine system functioning and interfering with organ morphogenesis and physiological functions. The development and regeneration of bone tissues have a complex hormonal regulation, and therefore, bone tissue cells can be considered potential targets for endocrine disruptors. In that regard, the aim of this research was to investigate the impact of ED exposure on the inflammatory response and oxidative stress in an experimental model of collagen-induced arthritis (CIA). Arthritis was induced by an emulsion of type II collagen (CII) and complete Freund’s adjuvant, which was administered intradermally on days 0 and 21. Mice from day 21 to day 35 received the following EDs by oral gavage: cypermethrin (CP), diethyl phthalate (DEP), vinclozolin (VCZ), 17α-ethinylestradiol (EE), perfluorooctanesulfonic acid (PFOS) and atrazine (ATR). ED exposure caused worsening of clinical signs (erythema and edema in the hind paws), histological and radiographic changes, as well as behavioral deficits, induced by CII injections. Furthermore, ED exposure significantly increased the degree of inflammation and oxidative damage induced by arthritis; this upregulation was more evident after exposure to ATR than to other EDs. The results from our study suggest that exposure to EDs may play a deleterious role in the progression of RA; therefore, exposure to EDs should be limited.

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“…Hashemi and colleagues reported no differences between NAC and placebo groups with respect to CRP, IL-6 and TNF-α (Hashemi et al 2019). Esalatmanesh and colleagues reported no differences between the NAC and placebo groups with respect to hs-CRP (Esalatmanesh et al 2022).…”

Section: Oral Nac In Rheumatic Diseases In Humansmentioning

confidence: 99%

“…In recent clinico-pharmacological studies on NAC (Zhang et al 2018;Hashemi et al 2019;Esalatmanesh et al 2022), clinical laboratory measurements were accompanied with measurements of biochemical parameters to study potential underlying mechanisms. Measured parameters included nitrite and nitrate as indicators of nitric oxide (NO) synthesis and malondialdehyde (MDA) as an indicator of oxidative stress (lipid peroxidation).…”

Section: Oral Nac In Rheumatic Diseases In Humansmentioning

confidence: 99%

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N-Acetyl-L-cysteine in human rheumatoid arthritis and its effects on nitric oxide (NO) and malondialdehyde (MDA): analytical and clinical considerations

Tsikas

Mikuteit

2022

Amino Acids

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N-Acetyl-L-cysteine (NAC) is an endogenous cysteine metabolite. The drug is widely used in chronic obstructive pulmonary disease (COPD) and as antidote in acetaminophen (paracetamol) intoxication. Currently, the utility of NAC is investigated in rheumatoid arthritis (RA), which is generally considered associated with inflammation and oxidative stress. Besides clinical laboratory parameters, the effects of NAC are evaluated by measuring in plasma or serum nitrite, nitrate or their sum (NOx) as measures of nitric oxide (NO) synthesis. Malondialdehyde (MDA) and relatives such as 4-hydroxy-nonenal and 15(S)-8-iso-prostaglandin F2α serve as measures of oxidative stress, notably lipid peroxidation. In this work, we review recent clinico-pharmacological studies on NAC in rheumatoid arthritis. We discuss analytical, pre-analytical and clinical issues and their potential impact on the studies outcome. Major issues include analytical inaccuracy due to interfering endogenous substances and artefactual formation of MDA and relatives during storage in long-term studies. Differences in the placebo and NAC groups at baseline with respect to these biomarkers are also a serious concern. Modern applied sciences are based on data generated using commercially available instrumental physico-chemical and immunological technologies and assays. The publication process of scientific work rarely undergoes rigorous peer review of the analytical approaches used in the study in terms of accuracy/trueness. There is pressing need of considering previously reported reference concentration ranges and intervals as well as specific critical issues such as artefactual formation of particular biomarkers during sample storage. The latter especially applies to surrogate biomarkers of oxidative stress, notably MDA and relatives. Reported data on NO, MDA and clinical parameters, including C-reactive protein, interleukins and tumour necrosis factor α, are contradictory in the literature. Furthermore, reported studies do not allow any valid conclusion about utility of NAC in RA. Administration of NAC patients with rheumatoid arthritis is not recommended in current European and American guidelines.

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Effects of N-acetylcysteine supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in rheumatoid arthritis patients: a randomized double-blind placebo-controlled trial

Cited by 14 publications

References 53 publications

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment

Toxic Effects of Endocrine Disruptor Exposure on Collagen-Induced Arthritis

N-Acetyl-L-cysteine in human rheumatoid arthritis and its effects on nitric oxide (NO) and malondialdehyde (MDA): analytical and clinical considerations

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