Berberine Decreased Inducible Nitric Oxide Synthase mRNA Stability through Negative Regulation of Human Antigen R in Lipopolysaccharide-Induced Macrophages

Abstract

Berberine, a major isoquinoline alkaloid found in medicinal herbs, has been reported to possess anti-inflammatory effects; however, the underlying mechanisms responsible for its actions are poorly understood. In the present study, we investigated the inhibitory effects of berberine and the molecular mechanisms involved in lipopolysaccharide (LPS)-treated RAW 264.7 and THP-1 macrophages and its effects in LPS-induced septic shock in mice. In both macrophage cell types, berberine inhibited the LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) protein expression, but it had no effect on iNOS mRNA transcription. Suppression of LPS-induced iNOS protein expression by berberine occurred via a human antigen R (HuR)-mediated reduction of iNOS mRNA stability. Molecular data revealed that the suppression on the LPS-induced HuR binding to iNOS mRNA by berberine was accompanied by a reduction in nucleocytoplasmic HuR shuttling. Pretreatment with berberine reduced LPS-induced iNOS protein expression and the cytoplasmic translocation of HuR in liver tissues and increased the survival rate of mice with LPS-induced endotoxemia. These results show that the suppression of iNOS protein expression by berberine under LPS-induced inflammatory conditions is associated with a reduction in iNOS mRNA stability resulting from inhibition of the cytoplasmic translocation of HuR.

Chinese Herbal Formula, Modified Danggui Buxue Tang, Attenuates Apoptosis of Hematopoietic Stem Cells in Immune-Mediated Aplastic Anemia Mouse Model

“…Palmatine plays an important role in osteoclast apoptosis by regulating the inducible nitric monoxide synthase (iNOS) system [ 20 ]. Berberine can also decrease cell apoptosis induced by LPS by suppressing iNOS protein expression [ 21 ]. Calycosin reduces oxidative stress by regulating the activation of the PI3K/Akt/GSK-3 β signaling pathway and suppressing osteoclastogenesis through inhibition of MAPK and NF- κ B activation [ 22 ].…”

Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

“…Under normal cellular and physiologic conditions, HuR is primarily located in the nucleus, but upon exposure to intrinsic and/or extrinsic stress, HuR can translocate to the cytoplasm where it stabilizes and increases the translation of target mRNAs. Chronic activation of HuR leads to an inflammatory phenotype which underlies HuR's contribution to many disease states, and is also thought to be a large part of HuR's ability to promote tumorigenesis (Di Marco et al, ; Matsye et al, ; Nabors, Gillespie, Harkins, & King, ; W. Peng et al, ; Shin et al, ). Beyond this promotion of tumorigenesis, HuR has also been shown to be a lynchpin for driving resistance to a variety of stressful conditions that cancer cells face (Amreddy et al, ; Badawi, Hehlgans, Pfeilschifter, Rodel, & Eberhardt, ; Blanco et al, ; Cai et al, ; Chand et al, ; Hostetter et al, ; G. L. Lin, Ting, Tseng, Juang, & Lo, ; Z. M. Liu, Tseng, Hong, & Huang, ; Mehta et al, ; Zarei et al, ; R. Zhang & Wang, ).…”

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

“…Although LP-BER enhanced drug concentration in liver and spleen compared to the free drug ( Figure 4 ) and showed antileishmanial activity ( Figure 5 ), it is noteworthy that the drug concentration in these organs was much lower than the in vitro IC 50 values (0.41 μg/mL, Table 4 ). As the antileishmanial activity of drugs is dependent on drug concentrations in organs where the parasites are located [ 52 ] (liver, spleen and BM for VL and skin lesions in the case of CL), this observation is indicating that either BER metabolites or BER immunomodulatory activities (macrophage-mediated effect) are also contributing to the efficacy of LP-BER, reinforcing, on one hand, the idea that several BER metabolites exert similar bioactivities [ 35 ], and, on the other hand, the immunomodulatory effect of BER via production of NO [ 9 ]. The low plasmatic levels obtained after i.p.…”