Abstract
Isorhamnetin is a flavonoid that is abundant in the fruit of Hippophae rhamnoides L. It is widely studied for its ability to modulate inflammatory responses. In this study, we evaluated the potential of isorhamnetin to prevent gram-negative sepsis. We investigated its efficacy using an Escherichia coli-induced sepsis model. Our study reveals that isorhamnetin treatment significantly enhances survival and reduces proinflammatory cytokine levels in the serum and lung tissue of E. coli-infected mice. Further, isorhamnetin treatment also significantly reduces the levels of aspartate aminotransferase, alanine amino transferase and blood urea nitrogen, suggesting that it can improve liver and kidney function in infected mice. Docking studies reveal that isorhamnetin binds deep in the hydrophobic binding pocket of MD-2 via extensive hydrophobic interactions and hydrogen bonding with Tyr102, preventing TLR4/MD-2 dimerization. Notably, binding and secreted alkaline phosphatase reporter gene assays show that isorhamnetin can interact directly with the TLR4/MD-2 complex, thus inhibiting the TLR4 cascade, which eventually causes systemic inflammation, resulting in death due to cytokine storms. We therefore presume that isorhamnetin could be a suitable therapeutic candidate to treat bacterial sepsis.
Highlights
Inflammation is an innate immune response against microbial infection
Based upon binding affinity and a molecular docking examination, we show for the first time, to our knowledge, that isorhamnetin can bind TLR4/MD-2 directly, preventing the activation of the TLR4 cascade, which is responsible for sepsis progression
It was previously reported that isorhamnetin can reduce inflammation by downregulating nitric oxide (NO) and cytokine production [19]
Summary
Inflammation is an innate immune response against microbial infection. If it persists for a long time, it can cause several fatal diseases, including sepsis. Sepsis is a clinical condition defined as a systemic inflammation in the body in response to microbial infection, which eventually leads to multiple organ failure. Sepsis is reported to be the leading cause of mortality across the globe, and the World Health Organization (WHO) devoted the year 2017 to prioritize this disease and its treatment strategies [1,2,3]. The organs and systems that are commonly affected by sepsis include the lung, abdomen, blood and kidneys, with associated incidences of 64%, 20%, 15% and 14%, respectively [3]. Pathophysiological studies reveal that the activation of toll-like receptors (TLRs) by microbes or microbial peptides represents the principle mechanism underlying the development of sepsis [3,4]
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