The oxygenated products of cryptotanshinone by biotransformation with Cunninghamella elegans exerting anti-neuroinflammatory effects by inhibiting TLR 4-mediated MAPK signaling pathway

Abstract

Background: Neuroin ammatory processes are critical in the development and progression of Alzheimer's disease (AD). The potent anti-neuroin ammatory inhibitors are expected as the candidates to treat AD. Cryptotanshinone (1), a major bioactive constituent in the traditional Chinese medicinal herb Dan-Shen Salvia miltiorrhiza Bunge, has been reported to possess remarkable pharmacological activities, especially anti-oxidation and anti-in ammation. Methods: Cryptotanshinone (1) was biotransformed with the fungus Cunninghamella elegans AS3.2028 to improve its bioactivities and physicochemical properties. The structures of transformed products were elucidated by comprehensive spectroscopic analysis including HRESIMS, NMR and ECD data. Their antineuroin ammatory activities were assessed by ELISA, transcriptome analysis, western blot, and immuno uorescence methods. Results: Three oxygenated products (2-4) at C-3 of cryptotanshinone (1) were obtained, among them 2 was a new compound. All of the biotransformed products (2-4) were found to inhibit signi cantly lipopolysaccharide-induced nitric oxide production in BV2 microglia cells with the IC 50 values of 0.16-1.16 μM, approximately 2-20 folds stronger than the substrate (1). These biotransformed products also displayed remarkably improved inhibitory effects on the production of in ammatory cytokines (IL-1β, IL-6, TNF-α, COX-2 and iNOS) in BV-2 cells via targeting TLR4 compared to substrate (1). The underlying mechanism of 2 was elucidated by comparative transcriptome analysis, which suggested that it reduced neuroin ammatory mainly through mitogen-activated protein kinase (MAPK) signaling pathway. Western blotting results revealed that 2 downregulated LPS-induced phosphorylation of JNK, ERK, and p38 in MAPK signaling pathway. Conclusion: The biotransformed products of cryptotanshinone exhibit potent anti-neuroin ammatory activities. These ndings provide a basal material for the discovery of candidates in treating AD.

Cryptotanshinone ameliorates CUS-induced depressive-like behaviors in mice

“…These results indicate that CPT can promote the transformation of microglia/macrophages from the M1- to the M2-type and thus exerts neuroprotective effects. Researches have reported that CPT can inhibit neuroinflammation and improve cognitive dysfunction by acting on the NF-κB signaling pathway [ 56 , 57 ]. Therefore, we speculated that CPT may inhibit neuroinflammation and exert neuroprotective effects by inhibiting the NF-κB signaling pathway.…”

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment

“…For one thing, bioactive compounds in TCM or TCM compound can reduce the synthetize of neurotoxic substances such as Aβ and Tau phosphorylation ( 31 ). For another thing, they can promote the clearance of toxic substances by increasing the toxic substance degradation enzyme, improving the blood-brain barrier function and promoting microglia phagocytosis ( 32 , 33 ). TCM also reduces neuronal apoptosis and loss of neurons caused by excessive autophagy ( 34 , 35 ).…”

Novel perspectives on the therapeutic role of cryptotanshinone in the management of stem cell behaviors for high-incidence diseases

“…In addition, the clinical trials of chemical drugs are summarized ( Table 1 ). CTS is being studied for a variety of pharmacological effects, including anti-inflammatory ( Wu et al, 2020 ; Liu et al, 2021a ), neuroprotective ( Mao et al, 2021 ), cardioprotective ( Wang et al, 2021e ), anti-fibrosis ( Lo et al, 2017 ; Zhang et al, 2020 ) and anti-tumor ( Dong et al, 2018 ; Han et al, 2019 ; Vundavilli et al, 2022 ). The diversity of pharmacological effects of CTS demonstrates unique potential for the treatment of high-incidence diseases.…”