Efficacy and Molecular Mechanism of Quercetin on Constipation Induced by Berberine via Regulating Gut Microbiota.

Berberine (BBR) is used to treat cancer, inflammatory conditions, and so on. But the side effects of BBR causing constipation should not be ignored. In clinical application, the combination of Amomum villosum Lour. (AVL) and BBR can relieve it. However, the effective ingredients and molecular mechanism of AVL in relieving constipation are not clear. A small intestine propulsion experiment was conducted in constipated mice to screen active ingredients of AVL. We further confirmed the molecular mechanism of action of the active ingredient on BBR-induced constipation. Quercetin (QR) was found to be the effective ingredient of AVL in terms of relieving constipation. QR can efficiently regulate the microbiota in mice suffering from constipation. Moreover, QR significantly raised the levels of substance P and motilin while lowering those of 5-hydroxytryptamine and vasoactive intestinal peptide; furthermore, it also increased the protein expression levels of calmodulin, myosin light-chain kinase, and myosin light chain. The use of QR in combination with BBR has an adverse effect-reducing efficacy. The study provides new ideas and possibilities for the treatment of constipation induced by BBR.

Plant Polyphenols Attenuate DSS-induced Ulcerative Colitis in Mice via Antioxidation, Anti-inflammation and Microbiota Regulation.

The pathogenesis of ulcerative colitis (UC) is associated with inflammation, oxidative stress, and gut microbiota imbalance. Although most researchers have demonstrated the antioxidant bioactivity of the phenolic compounds in plants, their UC-curing ability and underlying mechanisms still need to be further and adequately explored. Herein, we studied the antioxidation-structure relationship of several common polyphenols in plants including gallic acid, proanthocyanidin, ellagic acid, and tannic acid. Furthermore, the in vivo effects of the plant polyphenols on C57BL/6 mice with dextran-sulfate-sodium-induced UC were evaluated and the action mechanisms were explored. Moreover, the interplay of several mechanisms was determined. The higher the number of phenolic hydroxyl groups, the stronger the antioxidant activity. All polyphenols markedly ameliorated the symptoms and pathological progression of UC in mice. Furthermore, inflammatory cytokine levels were decreased and the intestinal barrier was repaired. The process was regulated by the antioxidant-signaling pathway of nuclear-erythroid 2-related factor 2. Moreover, the diversity of the intestinal microbiota, Firmicutes-to-Bacteroides ratio, and relative abundance of beneficial bacteria were increased. An interplay was observed between microbiota regulation and oxidative stress, immunity, and inflammatory response. Furthermore, intestinal barrier repair was found to be correlated with inflammatory responses. Our study results can form a basis for comprehensively developing plant-polyphenol-related medicinal products.

Fabrication of Co-Assembly from Berberine and Tannic Acid for Multidrug-Resistant Bacteria Infection Treatment.

Long-term antibiotic use induces drug resistance in bacteria. This has given rise to the challenge of refractory infections, which have become a global health threat. Berberine (BBR) and tannic acid (TA) from plants exhibit promising antibacterial activities and may overcome antibiotic resistance. However, poor solubility and/or low penetration capability have limited their application. Carrier-free co-assembled nanocomposites composed entirely of BBR and TA exhibit improved or new properties and produce improved efficacy. Herein, we demonstrated that an ordered nanostructure could be spontaneously co-assembled by the solvent evaporation method using the two natural products. These co-assembled berberine-tannic acid nanoparticles (BBR-TA NPs) exhibited the best antibacterial effect compared with the corresponding physical mixture, pristine BBR, and some first-line antibiotics (benzylpenicillin potassium-BP and ciprofloxacin-Cip) against Staphylococcus aureus (S. aureus) and multidrug-resistant Staphylococcus aureus (MRSA). Even if the concentration of BBR-TA NPs was as low as 15.63 µg/mL, the antibacterial rate against S. aureus and MRSA was more than 80%. In addition to the synergistic effect of the two compounds, the antibacterial mechanism underlying the nanostructures was that they strongly adhered to the surface of the bacterial cell wall, thereby inducing cell membrane damage and intracellular ATP leakage. Furthermore, the in vivo wound healing effect of BBR-TA NPs was verified using an MRSA wound infection mouse model. The BBR-TA NPs achieved the best efficacy compared with BP and Cip. Moreover, cytotoxic and histopathological evaluations of mice revealed that the nanodrug had good biological safety. This facile and green co-assembly strategy for preparing nanoparticles provides a feasible reference for the clinical treatment of bacterial infection.

Rhubarb polysaccharide and berberine co-assembled nanoparticles ameliorate ulcerative colitis by regulating the intestinal flora.

Introduction: Inflammatory bowel disease (IBD) affects about 7 million people globally, which is a chronic inflammatory condition of the gastrointestinal tract caused by gut microbiota alterations, immune dysregulation, genetic and environmental factors. Nanoparticles (NPs) deliver an active natural compound to a site harbored by disordered microbiota, they are used to interact, target and act intentionally on microbiota. Although there is accumulating evidence indicating that berberine and polysaccharide play an important role in IBD via regulating microbiota, there is limited research that presents a complete picture of exactly how their carrier-free co-assembled nanodrug affects IBD. Methods: The study establishes the carrier-free NPs formed by berberine and rhubarb polysaccharide based on the combination theory of Rheum palmatum L. and Coptis chinensis Franch., and characterizes the NPs. The IBD treatment efficacy of NPs are evaluated via IBD efficacy index, and explore the mechanism of NPs via 16S rRNA test and immunohistochemistry including occludin and zonula occludens-1. Results: The results showed that DHP and BBR were co-assembled to nanoparticles, and the BD can effectively relieve the symptoms of UC mouse induced by DSS via regulating gut microbiota and repair the gut barrier integrity, because BD have a longer retention on the colon tissue and react with the microbiota and mucus thoroughly. Interestingly, BD can enrich more probiotic than free BBR and DHP. Discussion: This design provides a better strategy and encourages future studies on IBD treatment via regulating gut microbiota and the design of novel plant polysaccharide based carrier-free co-assembly therapies.

Co-assembled nanocomplexes comprising epigallocatechin gallate and berberine for enhanced antibacterial activity against multidrug resistant Staphylococcus aureus.

Berberine (BBR), a major alkaloid in Coptis chinensis, and (-)-epigallocatechin-3-gallate (EGCG), a major catechin in green tea, are two common phytochemicals with numerous health benefits, including antibacterial efficacy. However, the limited bioavailability restricts their application. Advancement in the co-assembly technology to form nanocomposite nanoparticles precisely controls the morphology, electrical charge, and functionalities of the nanomaterials. Here, we have reported a simple one-step method for preparing a novel nanocomposite BBR-EGCG nanoparticles (BBR-EGCG NPs). These BBR-EGCG NPs exhibit improved biocompatibility and greater antibacterial effects both in vitro and in vivo relative to free-BBR and first-line antibiotics (i.e., benzylpenicillin potassium and ciprofloxacin). Furthermore, we demonstrated a synergistic bactericidal effect for BBR when combined with EGCG. We also evaluated the antibacterial activity of BBR and the possible synergism with EGCG in MRSA-infected wounds. A potential mechanism for synergism between S. aureus and MRSA was also explored through ATP determination, the interaction between nanoparticles and bacteria, and, then, transcription analysis. Furthermore, our experiments on S. aureus and MRSA confirmed the biofilm-scavenging effect of BBR-EGCG NPs. More importantly, toxicity analysis revealed that the BBR-EGCG NPs had no toxic effects on the major organs of mice. Finally, we proposed a green method for the fabrication of BBR-EGCG combinations, which may provide an alternative approach to treating infections with MRSA without using antibiotics.

Rhodiola rosea polysaccharides-based nanoparticles loaded with DOX boosts chemo-immunotherapy for triple-negative breast cancer by re-educating Tumor-associated macrophages.

Hydrophobic drug delivery vectors suffer significant challenges in cancer therapy, including efficient encapsulation and tumor targeting ability. In the present study, Rhodiola rosea polysaccharides (RHPs), which have the ability to modulate Tumor-associated macrophages and typical structural characteristics, were employed as an immunoactive vector for drug delivery. Folic acid (FA) and stearic acid (SA) were chemically modified to the backbone of RHPs to obtain the self-assembly and tumor-targeting behavior. Further, the hydrophobic drug, doxorubicin (DOX), was encapsulated in the RHPs derivatives (FA-RHPs-SA) with high efficiency. Additionally, the optimally formed DOX@FA-RHPs-SA had a uniform size distribution of approximately 196 nm and a pH-sensitive release capacity in different acidic conditions. In vitro experiments demonstrated that tumor cells could efficiently uptake DOX@FA-RHPs-SA. Furthermore, the modulatory function of the FA-RHPs-SA on RAW264.7 macrophages was also demonstrated in the transition from M0 to M1 phenotypes, and the M2 differentiated into the M1. Finally, the in vivo antitumor study revealed that the inhibitory effect of DOX@FA-RHPs-SA was superior to the DOX monotherapy treatment, and the new preparation functioned synergistically by inducing tumor cell apoptosis and modulating immune cell function. In conclusion, this study described an RHPs-based hydrophobic delivery vector and achieved an additional helpful antitumor effect by modulating Tumor-associated macrophages.