The effect of immunomodulatory properties of naringenin on the inhibition of inflammation and oxidative stress in autoimmune disease models: a systematic review and meta-analysis of preclinical evidence.

Abstract

Naringenin is a member of the flavonoid family that can perform many biological processes to treat a wide range of inflammatory diseases and pathological conditions related to oxidative stress (OS). Naringenin immunomodulatory activities have been the subject of recent research as an effective alternative treatment for autoimmune disorders. The effects of naringenin on the levels of inflammatory biomarkers and OS factors in animal models of autoimmune disorders (ADs) were studied in this meta-analysis. Up until January 2022, electronic databases such as Cochrane Library and EMBASE, PubMed, Web of Science, and Scopus were used to conduct a comprehensive literature search in English language. To evaluate the effect of naringenin on inflammatory mediators, such as TNF-α, IL-6, IL-β, IFN-γ, NF-κB, and nitric oxide, and OS biomarkers, such as CAT, SOD, GPx, GSH and MDA, in AD models, we measured the quality assessment and heterogeneity test using the PRISMA checklist protocol and I2 statistic, respectively. A random-effects model was employed based on the heterogeneity test, and then pooled data were standardized as mean difference (SMD) with a 95% confident interval (CI). We excluded all clinical trials, cell experiment studies, animal studies with different parameters, non-autoimmune disease models, and an inadequate series of studies for quantitative synthesis. Finally, from 627 potentially reports, 12 eligible studies were included in the meta-analysis. Data were collected from several groups. Of these, 153 were in the naringenin group and 149 were in the control group. Our meta-analysis of the pooled data for the parameters of inflammation and OS indicated that naringenin significantly reduced the levels of NF-κB (SMD -3.77, 95% CI [-6.03 to -1.51]; I2 = 80.1%, p = 0.002), IFN-γ (SMD -6.18, 95% CI [-8.73 to -3.62]; I2 = 53.7%, p = 0.115), and NO (SMD -3.97, 95% CI [-5.50 to -2.45]; I2 = 73.4%, p = 0.005), IL-1β (SMD -4.23, 95% CI [-5.09 to -3.37]; I2 = 0.0%, p = 0.462), IL-6 (SMD -5.84, 95% CI [-7.83 to -3.85]; I2 = 86.5%, p < 0.001), and TNF-α (SMD -5.10, 95% CI [-6.34 to -3.86]; I2 = 74.7%, p < 0.001). These findings also demonstrated the efficacy of naringenin on increasing the levels of CAT (SMD 4.19, 95% CI [1.33 to 7.06]; I2 = 79.9%, p = 0.007), GSH (SMD 4.58, 95% CI [1.64 to 7.51]; I2 = 90.5%, p < 0.001), and GPx (SMD 9.65, 95% CI [2.56 to 16.74]; I2 = 86.6%, p = 0.001) and decreasing the levels of MDA (SMD -3.65, 95% CI [-4.80 to -2.51]; I2 = 69.4%, p = 0.001) than control groups. However, treatment with naringenin showed no statistically difference in SOD activity (SMD 1.89, 95% CI [-1.11 to 4.89]; I2 = 93.6%, p < 0.001). Overall, our findings revealed the immunomodulatory potential of naringenin as an alternative treatment on inhibition of inflammation and OS in several autoimmune-related diseases. Nevertheless, regarding the limitation of clinical trials, strong preclinical models and clinical settings in the future are needed that address the effects of naringenin on ADs. Before large-scale clinical studies, precise human pharmacokinetic investigations are required to determine the dosage ranges and evaluate the initial safety profile of naringenin.