Protective Effect of Casperome®, an Orally Bioavailable Frankincense Extract, on Lipopolysaccharide- Induced Systemic Inflammation in Mice

Konstantin Loeser, Semjon Seemann, Stefanie König, Isabell Lenhardt, Mona Abdel-Tawab, Andreas Koeberle, Oliver Werz, Amelie Lupp, Konstantin Loeser, Semjon Seemann, Stefanie König, Isabell Lenhardt, Mona Abdel-Tawab, Andreas Koeberle, Oliver Werz, Amelie Lupp

Abstract

Introduction: Despite recent advances in critical care, sepsis remains a crucial cause of morbidity and mortality in intensive care units. Therefore, the identification of new therapeutic strategies is of great importance. Since ancient times, frankincense is used in traditional medicine for the treatment of chronic inflammatory disorders such as rheumatoid arthritis. Thus, the present study intends to evaluate if Casperome® (Casp), an orally bioavailable soy lecithin-based formulation of standardized frankincense extract, is able to ameliorate systemic effects and organ damages induced by severe systemic inflammation using a murine model of sepsis, i.e., intraperitoneal administration of lipopolysaccharides (LPS). Methods: Male 60-day-old mice were assigned to six treatment groups: (1) control, (2) LPS, (3) soy lecithin (blank lecithin without frankincense extract), (4) Casp, (5) soy lecithin plus LPS, or (6) Casp plus LPS. Soy lecithin and Casp were given 3 h prior to LPS treatment; 24 h after LPS administration, animals were sacrificed and health status and serum cytokine levels were evaluated. Additionally, parameters representing liver damage or liver function and indicating oxidative stress in different organs were determined. Furthermore, markers for apoptosis and immune cell redistribution were assessed by immunohistochemistry in liver and spleen. Results: LPS treatment caused a decrease in body temperature, blood glucose levels, liver glycogen content, and biotransformation capacity along with an increase in serum cytokine levels and oxidative stress in various organs. Additionally, apoptotic processes were increased in spleen besides a pronounced immune cell infiltration in both liver and spleen. Pretreatment with Casp significantly improved health status, blood glucose values, and body temperature of the animals, while serum levels of pro-inflammatory cytokines and oxidative stress in all organs tested were significantly diminished. Finally, apoptotic processes in spleen, liver glycogen loss, and immune cell infiltration in liver and spleen were distinctly reduced. Casp also appears to induce various cytochromeP450 isoforms, thus causing re-establishment of liver biotransformation capacity in LPS-treated mice. Conclusion: Casp displayed anti-inflammatory, anti-oxidative, and hepatoprotective effects. Thus, orally bioavailable frankincense extracts may serve as a new supportive treatment option in acute systemic inflammation and accompanied liver dysfunction.

Keywords: cytokines; frankincense; lipopolysaccharides; liver function; oxidative stress; systemic inflammation.

Figures

FIGURE 1
FIGURE 1
Clinical severity score (A), blood glucose values (B), changes in body temperatures (C), changes in b.wt. (D), spleen (E), and adrenal weights (F). Mice were administered either vehicle (control), soy lecithin (Phyto), Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Data are given as means ± SEM, n = 8 for each group. ∗, significantly different from controls; +, significantly different from LPS-treated animals; o, significantly different from soy lecithin plus LPS-treated animals (p ≤ 0.05; Mann–Whitney U-test followed by Holm–Bonferroni correction).
FIGURE 2
FIGURE 2
Serum concentrations of TNF-α (A), IL-6 (B), IL-10 (C), and ALAT (D). Mice were administered either vehicle (control), soy lecithin (Phyto), Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Data are given as means ± SEM, n = 8 for each group. ∗, significantly different from controls; +, significantly different from LPS-treated animals; o, significantly different from soy lecithin plus LPS-treated animals (p ≤ 0.05; Mann–Whitney U-test followed by Holm–Bonferroni correction).
FIGURE 3
FIGURE 3
Tissue content of LPO in hearts (A), lungs (B), kidneys (C), livers (D), and spleens (E), and concentration of GSH in spleen tissue (F) as a measure of oxidative stress in the organs. Mice were administered either vehicle (control), soy lecithin (Phyto), Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Data are given as means ± SEM, n = 8 for each group. ∗, significantly different from controls; +, significantly different from LPS-treated animals; o, significantly different from soy lecithin plus LPS-treated animals (p ≤ 0.05; Mann–Whitney U-test followed by Holm–Bonferroni correction).
FIGURE 4
FIGURE 4
Cleaved caspase-3 (A–C), CD3 (D–F), and CD68 (G–I) expression in the spleens of control (A,D,G), LPS (B,E,H), or Casp plus LPS (C,F,I)-treated mice. Mice were administered either vehicle (control), soy lecithin, Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Representative photomicrographs from one of eight different tissue samples from control mice, LPS-treated, and LPS plus Casp-treated animals are shown. Photomicrographs from soy lecithin- or Casp-only-treated mice and from soy lecithin plus LPS-treated mice are not depicted separately since they did not differ from controls or LPS-only-treated mice, respectively. Immunohistochemistry (red–brown color), counterstaining with hematoxylin; original magnification: ×400. Arrows in B and C mark cleaved caspase-3-positive apoptotic cells, arrowheads indicate tingible body macrophages; arrows in G, H, and I mark CD68-positive monocytes/macrophages.
FIGURE 5
FIGURE 5
TNF-α (A–C) and iNOS (D–F) expression in the spleens of control (A,D), LPS (B,E), or Casp plus LPS (C,F)-treated mice. Mice were administered either vehicle (control), soy lecithin, Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Representative photomicrographs from one of eight different tissue samples from control mice, LPS-treated, and LPS plus Casp-treated animals are shown. Photomicrographs from soy lecithin- or Casp-only-treated mice and soy lecithin plus LPS-treated mice are not depicted separately since they did not differ from controls or LPS-only-treated mice, respectively. Immunohistochemistry (red–brown color), counterstaining with hematoxylin; original magnification: ×400. Arrows in A–C mark TNF-α-positive monocytes/macrophages, arrows in E and F indicate iNOS-positive neutrophils, respectively.
FIGURE 6
FIGURE 6
CD3 (A–C) and F4/80 (D–F) expression in the spleens of control (A,D), LPS (B,E), or Casp plus LPS (C,F)-treated mice. Mice were administered either vehicle (control), soy lecithin, Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Representative photomicrographs from one of eight different tissue samples from control mice, LPS-treated, and LPS plus Casp-treated animals are shown. Photomicrographs from soy lecithin- or Casp-only-treated mice and soy lecithin plus LPS-treated mice are not depicted separately since they did not differ from controls or LPS-only-treated mice, respectively. Immunohistochemistry (red–brown color), counterstaining with hematoxylin; original magnification: ×400. Arrows in A–C mark CD3-positive T-lymphocytes, arrows in D–F indicate F4/80-positive macrophages, respectively.
FIGURE 7
FIGURE 7
iNOS (A–C), TNF-α expression (D–F), and glycogen content (G–I) in the livers of control (A,D,G), LPS (B,E,H), or Casp plus LPS (C,F,I)-treated mice. Mice were administered either vehicle (control), soy lecithin, Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Representative photomicrographs from one of eight different tissue samples from control mice, LPS-treated, and LPS plus Casp-treated animals are shown. Photomicrographs from soy lecithin- or Casp-only-treated mice and soy lecithin plus LPS-treated mice are not depicted separately since they did not differ from controls or LPS-only-treated mice, respectively. A–F: Immunohistochemistry (red–brown color), counterstaining with hematoxylin; G–I: periodic acid-Schiff staining; original magnification: ×400. Arrows in B mark iNOS-positive neutrophils, arrows in E and F indicate TNF-α-positive monocytes/macrophages.
FIGURE 8
FIGURE 8
CYP 1A1 (A–C), CYP2B1 (D–F), and CYP3A2 (G–I) expression in the livers of control (A,D,G), LPS (B,E,H), or Casp plus LPS (C,F,I)-treated mice. Mice were administered either vehicle (control), soy lecithin, Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). Representative photomicrographs from one of eight different tissue samples from control mice, LPS-treated, and LPS plus Casp-treated animals are shown. Photomicrographs from soy lecithin- or Casp-only-treated mice and soy lecithin plus LPS-treated mice are not depicted separately since they did not differ from controls or LPS-only-treated mice, respectively. Immunohistochemistry (red–brown color), counterstaining with hematoxylin; original magnification: ×400. CYP expression was mainly confined to the hepatocytes around the central veins (asterisks).
FIGURE 9
FIGURE 9
Biotransformation capacity as determined by a panel of model reactions for different CYP isoforms. Mice were administered either vehicle (control), soy lecithin (Phyto), Casp, LPS (control + LPS), soy lecithin + LPS, or Casp plus LPS (Casp + LPS). ECOD (A), BROD (B), EROD (C), MROD (D), PROD (E), and EMND (F) were determined in the 9000 × g supernatants of the livers. Data are given as means ± SEM, n = 8 for each group. ∗, significantly different from controls; +, significantly different from LPS-treated animals; o, significantly different from soy lecithin plus LPS-treated animals (p ≤ 0.05; Mann–Whitney U-test followed by Holm–Bonferroni correction).
FIGURE 10
FIGURE 10
Effect of Casp on cytokine release and cytotoxicity in human monocytes. (A) Human primary monocytes were pre-incubated with vehicle or compounds (Casp; dexamethasone, dex) for 30 min prior to stimulation with LPS for 4 (TNF-α, IL-8) or 18 h (IL-6, IL-10). Formed cytokines were measured by ELISA. Data are means ± SEM; n = 3; ∗∗∗p < 0.001; ∗∗p < 0.01; ∗p < 0.05; inhibitor vs. stimulated control (100%), one-way ANOVA plus Bonferroni test. (B) Effect of Casp on cell viability. Intact human monocytes were incubated with compounds (Casp; staurosporine, stsp) or vehicle for 24 h and cell viability was analyzed by MTT assay. Data are means ± SEM; n = 3; ∗p < 0.05; inhibitor vs. vehicle control (100%), one-way ANOVA plus Bonferroni test.

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