| BackgroundSystemic Lupus Erythematosus (SLE) is an autoimmune disease typically with multi-system involvement, mainly characterized with antinuclear antibodies and other auto-antibodies appear in serum and multi-system damage and multi-system damage. The relationship between oxidative stress imbalance and SLE has been proved by many studies recent years. As an autoimmune disease with high incidence, the pathogenesis of SLE is related to damage of free radicals generated by oxidative stress.Oxidative stress is a balance, which would be destroyed if oxidation factors surpass the scavenging ability of antioxidant system under pathological conditions. And this is also called oxidative stress, causing damage to lipids, proteins, cell membranes and DNA. Reactive oxygen species (ROS) are major active substances that cause pathological damage with rather complicated scavenging mechanism. It is quite difficult to directly detect ROS, while nitric oxide (NO) and malondialdehyde (MDA) levels in serum are conventional indicators of excessive oxidation.8-epi-PGF2? is a recently discovered sensitive indicator, which can reflect oxidative stress and damage degree of free radicals, and is a stable chemical representing the extent of lipid peroxidation. Antioxidant systems in the body of human beings mainly include Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSH-PX). These antioxidants can antagonize ROS, reduce toxic peroxides to nontoxic hydroxyl compounds, promote the decomposition of H2O2, and thus protect the structure and function of cell membranes from interference and damage caused by peroxides.Considering that oxidative stress is closely related to autoimmune diseases like SLE, many research organizations focus on the study of SLE anti-oxidant treatments. N-acetylcysteine (NAC), which is derivative from an unnecessary amino acid L-cysteine acetylation, is a classic antioxidant. It has direct interference on various free radicals generation and ability to scavenge generated free radicals, and can regulate the activity of cell metabolism. Meanwhile, NAC increases the amount of glutathione in the body, is also anti-apoptotic, inhibits inflammatory nuclear factor-kappa B, has a wide range of biological activity, and plays an important role in processes including inflammation, immune response and cell growth regulation.The first randomized double blind case-control stiduy of N-acetyl cysteine (NAC) in the treatment of SLE was published in Arhtritis Rheum magazine published in 2012.Then the American scholar also has carried on the NAC treatment of SLE clinical observation, marked the NAC may become one of the treatment of SLE. But there are no domestic related research materials.The purpose of this subject is to investigate NAC treatment the curative effect of SLE domestic Han population. But because of ethical factors, not the placebo group, but the coordination of NAC and hydroxychloroquine sulfate in the treatment of SLE was observed, Then explore the advantages of joint treatment and the curative effect of NAC for the treatment of SLE.The research goal is to find more clinical therapy choice without iglucocorticoids in treatment of SLE.In order to observe the efficacy of NAC in SLE early-stage anti-oxidative treatment, mouse model was used to stimulate the pathophysiology of SLE. Antioxidant NAC was applied to MRL/lpr mice. In order to explore the impact and effects of NAC treatment on SLE oxidative stress, changes in serum levels of NO, MDA, SOD and GSH-PX in MRL/lpr mice were observed, and changes in serum ds-DNA level and urinary protein were also tested. Meanwhile, in order to analyze the effect of NAC on SLE acute phase, patients with mild SLE were treated with non-glucocorticoid containing NAC. Research ObjectivesPart 1. Animal Experiments1.Understand the characters of lupus early-stage oxidative stress by observing the changes of serum oxidative stress indicators in spontaneous lupus MRL/lpr mice.2.Preliminary explore the effect and efficacy of antioxidant NAC on oxidative stress indicators in spontameous lupus MRL/lpr mice.Part 2. Clinical Experiments1.Observe the short-term changes of NO, GSH,8-iso-PGF2a, ESR, Ds-DNA, IgG and systemic lupus erythematosus disease assessment indices (SLEDAI) after using NAC for SLE treatment.2.Investigate whether short-term efficacy can be increased by treating SLE patients with NAC in combination with non-glucocorticoid. Research MethodsPart 1. Animal ExperimentsThe study had 3 groups:The normal control group (BALB/c mice) had six mice. MRL/lpr group had 20 mice, which were randomly divided into non-intervention and intervention groups with 10 mice each. Mice in intervention group were given NAC 150 mg intra-peritoneal injection daily for 30 days. Mice in normal control group and observation group were given 0.9% NaCl intra-peritoneal injection daily for 30 days. Sufficient amounts of urine and serum samples were obtained by killing the mice after 30 days to test changes of urinary protein and anti-dsDNA antibody respectively. Serum levels of NO, MDA, SOD and GSH-PX were measured respectively by itrate reductase method, thiobarbituric acid method, xanthine oxidase-hydroxylamine method, chemical colorimetric method for mice in every group. The changes in the levels of these indicators were observed and analyzed in order to explore the NAC efficacy on SLE.Part 2:Clinical Experiments65 patients with mild SLE were divided into control group with 28cases and observation group with 35 cases. All the patients were treated with hydroxychloroquine sulfate while patients in observation group were treated with NAC (1200mg/daily) additionally. Changes of serum NO, GSH,8-iso-PGF2a, ESR, Ds-DNA, IgG and SLEDAI were tested before and 6 months after treatments.ResultsPart 1. Animal ExperimentThe MDA (12.35±2.56 nmol/mL) and NO (51.23±22.15 umol/L) levels in lupus mice were significantly higher than the MDA (5.26 ±1.89 nmol/ml) and NO (32.36 ±18.56 umol/L) in control group (P<0.05). While the SOD (51.05 ±12.35 U/mL) and GSH-PX (155.19±32.48 U/mL) were significantly lower than the SOD (75.41 ±20.54 U/mL) and GSH-PX (195.34 ±23.02 U/mL) in control group (P<0.05).Serum MDA and NO levels in lupus mice were positively correlated with anti-dsDNA antibody (r=0.53290.66752, P<0.05) while GSH-PX and SOD were negatively correlated (r=-0.6476,-0.5746, P<0.05).After 4-week intervention with NAC, MDA and NO levels in lupus mice in intervention group were 11.23±1.64 nmol/mL and 46.28±19.35 umol/L respectively, significantly lower than MDA (14.12±3.20 nmol/mL) and NO (32.36 ±18.56 umol/L) in non-intervention group (P<0.05). SOD and GSH-PX levels in intervention group were 83.25±21.46 U/mL and 221.30±23.85 U/mL respectively, significantly higher than SOD (60.12±22.41 U/mL) and GSH-PX (183.62±22.14 U/mL) in non-intervention group (P<0.05).After 4-week intervention with NAC, urinary protein level of 102.57±18.21ng/mL in lupus mice intervention group was significantly lower than that (126.24±21.32 ng/mL) in non-intervention group (P<0.05). However, serum ds-DNA level (15.40±2.10 ng/mL) in intervention group was significantly lower than that (18.02 ±2.32ng/ml) in non-intervention group (P<0.05).Part 2. Clinical ExperimentsAfter 6-month treatment, NO (36.45±8.4 umol/L) and 8-iso-PGF2a (41.26±8.36 ug/L) of SLE patients in observation group significantly decreased compared with NO (56.53±8.9 umol/L) and 8-iso-PGF2a (65.32±10.23 ug/L) levels before treatment (P<0.05), while GSH level increased obviously (1.01±3.26 mg/g vs.0.45±0.23 mg/g) (P<0.05).After 6-month SLE treatment for control group, there was no significant difference for various indicators (NO 50.37±8.9 umol/L,8-iso-PGF2a 55.65±8.45 ug/L, GSH 0.62±0.34 mg/g) compared with those (NO 57.05±7.8 umol/L, 8-iso-PGF2a63.59± 11.36 ug/L, GSH 0.49+0.31 mg/g) before treatment (P>0.05).SLEDAI (3.78± 1.20) in observation group 6 months after SLE treatment decreased obviously compared with that (7.33±1.41) before treatment (P<0.05); SLEDAl (5.50±0.92) in control group 6 months after SLE treatment also decreased obviously compared with that (7.50±.41) before treatment (P<0.05).IgG levels in observation group and control group before and 6 months after treatment had no significant difference (19.64±6.83 g/L vs.23.22±7.23 g/L; 20.11±5.69 g/L vs.24.95±8.21 g/L) (P>0.05).and C3 levels in observation group and control group before and 6 months after treatment had no significant difference too (0.82±0.24g/lVS0.85±0.32g/l;0.73±0.21 g/1 VS0.72±0.26g/l) (P>0.05).ESR (38.65±0.36 mm/h) and ds-DNA (45.36±16.32 IU/L) in observation group 6 months after treatment decreased obviously as compared with ESR (55.11±13.56 mm/h) and ds-DNA (78.56±15.36 IU/L) before treatment (P<0.05). For control group, however, various indicators had no significant change before (ESR 56.39±14.20 mm/h, ds-DNA 75.63±14.35 IU/L) and 6 months after (ESR 48.67±10.54 mm/h, ds-DNA 60.38±11.85 IU/L) treatment (P>0.05).ConclusionThere was imbalance between oxidant and antioxidant in the bodies of lupus model mice. The degree of oxidation was higher than normal control group, and the degree of oxidative stress was related to lupus disease.NAC is able to relieve oxidative stress caused by lupus.NAC has a certain role in controlling the patients' conditions with early-stage mild SLE, and has efficacy in decreasing the early activity of SLE. |
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