title: Kaempferol and Chrysin Synergies to Improve Septic Mice Survival.
abstract: Previously, we reported the role of synergy between two flavonoids-namely, chrysin and kaempferol-in inhibiting the secretion of a few major proinflammatory mediators such astumor necrosis factor-alpha (TNF-α),prostaglandin E₂ (PGE₂), and nitric oxide (NO) from lipopolysaccharide (LPS)-induced RAW 264.7 cells. The present study aims to evaluate the effects of this combination on a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Severe sepsis was induced in male ICR mice (n= 7) via the CLP procedure. The effects of chrysin and kaempferol combination treatment on septic mice were investigated using a 7-day survival study. The levels of key proinflammatory mediators and markers-such asaspartate aminotransferase(AST), TNF-α, and NO-in the sera samples of the septic mice were determined via ELISA and fluorescence determination at different time point intervals post-CLP challenge. Liver tissue samples from septic mice were harvested to measure myeloperoxidase (MPO) levels using a spectrophotometer. Moreover, intraperitoneal fluid (IPF) bacterial clearance and total leukocyte count were also assessed to detect any antibacterial effects exerted by chrysin and kaempferol, individually and in combination. Kaempferol treatment improved the survival rate of CLP-challenged mice by up to 16%. During this treatment, kaempferol expressed antibacterial, antiapoptotic and antioxidant activities through the attenuation of bacterial forming units, AST and NO levels, and increased polymorphonuclear leukocyte (PMN) count in the IPF. On the other hand, the chrysin treatment significantly reduced serum TNF-α levels. However, it failed to significantly improve the survival rate of the CLP-challenged mice. Subsequently, the kaempferol/chrysin combination treatment significantly improved the overall 7-day survival rate by 2-fold-up to 29%. Kaempferol and chrysin revealed some synergistic effects by acting individually upon multiple pathophysiological factors involved during sepsis. Although the kaempferol/chrysin combination did not exhibit significant antibacterial effects, it did exhibit anti-inflammatory and antioxidant activities, which translate to significant improvement in the survival rate of septic animals. These findings suggest the potential application of this combination treatment as a beneficial adjuvant supplement strategy in sepsis control.
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia. omar_harastany@yahoo.com.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Harasstani
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia. chauling@upm.edu.my.
authors.forename: Chau Ling
authors.initials: CL
authors.lastname: Tham
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia. daudaia@upm.edu.my.
authors.forename: Daud A
authors.initials: DA
authors.lastname: Israf
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression; D044949:Kaempferols / Q000494:pharmacology*; D007958:Leukocyte Count; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000097:blood; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D005419:Flavonoids; D044949:Kaempferols; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C043561:chrysin; C006552:kaempferol; D009195:Peroxidase; D001219:Aspartate Aminotransferases
keywords: chrysin; kaempferol; polymicrobial sepsis