Differential Regulation of NF‐κB and Nrf2 by Bojungikki‐Tang Is Associated with Suppressing Lung Inflammation

Abstract

Bojungikki-tang (BT), an Asian herbal remedy, has been prescribed to increase the vitality of debilitated patients. Since a compromised, weakened vitality often leads to illness, BT has been widely used to treat various diseases. However, little is known about the mechanism by which BT exerts its effect. Given that BT ameliorates inflammatory pulmonary diseases including acute lung injury (ALI), we investigated whether BT regulates the function of key inflammatory factors such as NF-κB and Nrf2, contributing to suppressing inflammation. Results show that BT interrupted the nuclear localization of NF-κB and suppressed the expression of the NF-κB-dependent genes in RAW 264.7 cells. In similar experiments, BT induced the nuclear localization of Nrf2 and the expression of the Nrf2-dependent genes. In a lipopolysaccharide-induced ALI mouse model, a single intratracheal administration of BT to mouse lungs ameliorated alveolar structure and suppressed the expression of proinflammatory cytokine genes and neutrophil infiltration to mouse lungs. Therefore, our findings suggest that suppression of NF-κB and activation of Nrf2, by which BT suppresses inflammation, are ways for BT to exert its effect.

Spiraea prunifolia var. simpliciflora Attenuates Oxidative Stress and Inflammatory Responses in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury and TNF-α-Stimulated NCI-H292 Cells

“…Moreover, we confirmed that SP pretreatment showed higher expression levels of HO-1 and NQO1 in lung tissue than those of LPS-treated mice. The phenomenon suggested that SP itself might promote the nuclear translocation of Nrf2 with an up-regulation of HO-1 and NQO1 ( Figures 5 and 8) and these results were consistent with results of previous studies [59,60]. Therefore, our results suggest that the protective effects of SP on the LPS-induced oxidative stress may be closely associated with the activation of Nrf2 and its potent antioxidant activities.…”

“…In response to LPS-induced oxidative stress, the HO-1 and NQO1 levels were slightly increased in the LPS-treated THP-1 cells [58]. In in vivo studies, LPS treatment caused ROS-mediated oxidative stress that induced a compensatory increase of HO-1 and NQO1 in the LPS-induced ALI model [59,60]. Consistent with these results, LPS-treated mice showed a slight increase of HO-1 and NQO1 levels in lung tissues.…”

Safety and Efficacy of Bojungikki-Tang in Advanced NSCLC Patients Receiving Treatment with Immune Checkpoint Inhibitors: Protocol for a Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Trial

“…Moreover, BJIKT treatment has been shown to inhibit the production of proinflammatory cytokines and is considered a beneficial treatment for restoring the immunological status of cancer patients experiencing physical and psychological stress [14][15][16][17]. In addition, BJIKT enhances weakened immune function and suppresses the enhanced immune function attributable to the inflammatory response, suggesting that this medicine has a bidirectional immunomodulatory effect that compensates for both excess and deficiency conditions [18][19][20]. Although several studies have reported on the safety of BJIKT [21][22][23][24][25][26][27][28][29], none has evaluated the irAEs of BJIKT in patients with advanced NSCLC treated with ICIs.…”

“…The study exclusion criteria are as follows: (1) diagnosis of a new primary cancer within the last five years; (2) treatment with an immunosuppressive drug within the last two weeks or ICI treatment within the last six weeks; (3) treatment with antibiotics within the last two weeks; (4) current treatment with thiazide or a loop diuretic; (5) the presence of hypokalemia; (6) a history of interstitial lung disease in the patient's medical history; (7) confirmed EGFR or ALK gene mutations; (8) active autoimmune disease requiring systemic therapy within the last two years; (9) uncontrolled diabetes (i.e., diabetes that is uncontrolled with insulin or oral medication, based on fasting blood sugar levels); (10) uncontrolled hypertension; (11) heart defect; (12) active or untreated human immunodeficiency virus, tuberculosis, hepatitis B, or hepatitis C; (13) significant hematologic disease within six months before randomization; (14) abdominal cavity, esophageal atresia, or gastrointestinal-duct perforation within six months before randomization; (15) unresolved toxicity with a Common Terminology Criteria for Adverse Events (CTCAE) v5.0 level of >1 resulting from previous therapy at the start of the trial therapy; (16) serious hypersensitivity to ingredients in the investigational drug; (17) pregnancy or lactation; (18) among fertile women, lack of consent to use effective contraception for at least five months after the final administration of atezolizumab during the course of the clinical trial; (19) use of an oriental medicine or functional food that was determined by the investigator as having a potential to affect the trial or the patient's safety within four weeks before initial treatment with the investigational drug; (20) participation in a clinical trial within four weeks before the first administration of the investigational drug; and (21) patients deemed unsuitable for this clinical trial by the investigator for various reasons, including serious infectious disease and organ failure.…”

“…This herbal medicine is composed of Ginseng Radix, Atractylodis Rhizoma Alba, Astragali Radix, Angelicae Gigantis Radix, Zizyphi Fructus, Bupleuri root, Citri Unshius Pericarpium, Cimicifugae Rhizoma, Zingiberis Rhizoma Recens, and Glycyrrhizae Radix et Rhizoma. It has a bidirectional immunomodulatory effect that compensates for both excess and deficient conditions in treating cancer [14][15][16][17][18][19][20]. Many studies have reported on the safety of BJIKT, including its toxicity profile and long-term administration in cancer patients [21][22][23][24][25][26][27][28][29].…”