Rhamnetin, a Natural Flavonoid, Ameliorates Organ Damage in a Mouse Model of Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis

Abstract

In sepsis, the persistence of uncontrolled inflammatory response of infected host cells eventually leads to severe lung and organ failure and, ultimately, death. Carbapenem-resistant Acinetobacter baumannii (CRAB), causative bacteria of sepsis and lung failure in acute cases, belongs to a group of critical pathogens that cannot be eradicated using the currently available antibiotics. This underlines the necessity of developing new modes of therapeutics that can control sepsis at the initial stages. In this study, we investigated the anti-inflammatory activities in vitro and in vivo and the antiseptic effects of rhamnetin, a naturally occurring flavonoid. We found that among its isoforms, the potency of rhamnetin was less explored but rhamnetin possessed superior anti-inflammatory activity with least cytotoxicity. Rhamnetin showed significant anti-inflammatory effects in lipopolysaccharide-, CRAB-, and Escherichia coli (E. coli)-stimulated mouse macrophages by inhibiting the release of interleukin-6 and nitric oxide. In a mouse model of sepsis infected with clinically isolated CRAB or E. coli, rhamnetin significantly reduced the bacterial burden in the organs. In addition, normalized pro-inflammatory cytokine levels in lung lysates and histological analysis of lung tissue indicated alleviation of lung damage. This study implies that a potent natural product such as rhamnetin could be a future therapeutic for treating carbapenem-resistant gram-negative sepsis.

Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats

“…The flavonoid polyphenol quercetin upregulates neuron gene expression [ 86 ]. The flavonoid rhamnetin decreases organ failure in Gram-negative bacterial sepsis in mice [ 87 ]. Similarly, the flavonoids luteolin and icariin increase survival against polymicrobial sepsis [ 36 , 37 ].…”

The Most Potent Natural Pharmaceuticals, Cosmetics, and Food Ingredients Isolated from Plants with Deep Eutectic Solvents

“…Studies revealed that it can be a promising and cheap source of flavonoids. , Flavonoids have great potential as anticancer and anti-inflammatory pharmaceuticals, as well as antiaging agents in cosmetics. Examples of these compounds, extracted from plants with DESs, are presented in Table . ,− …”

Protective Effects of Rhamnetin in Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis Model and the Underlying Mechanism

“…We identified the anti-inflammatory activities of various flavonols, such as isorhamnetin, rhamnetin, and tamarixetin, which inhibit the production of pro-inflammatory cytokines in LPS-stimulated macrophages. [30][31][32]. In particular, rhamnetin, an O-methylated flavonol, can reduce inflammatory responses in the E. coli and CRAB-induced septic shock mouse model [31] (Figure 1).…”

“…[30][31][32]. In particular, rhamnetin, an O-methylated flavonol, can reduce inflammatory responses in the E. coli and CRAB-induced septic shock mouse model [31] (Figure 1). However, the underlying mechanism for the anti-inflammatory and antiseptic effects of rhamnetin has not been elucidated yet.…”

“…Rhamnetin is a flavonoid derived from Rhamnus petiolaris, Syzygium aromaticum, Coriandrum sativum, and Prunus cerasus [33]. Rhamnetin is O-methylated at position 7 of ring A and exerts various biological effects, including anti-inflammatory [34], anticancer [35,36], and antiseptic activities [31]. We previously observed that rhamnetin showed recovery effects on organ dysfunction and cytokine release in a CRAB-induced sepsis mouse model.…”