Bone-Targeted Supramolecular Nanoagonist Assembled by Accurate Ratiometric Herbal-Derived Therapeutics for Osteoporosis Reversal.

Developing novel strategies for defeating osteoporosis has become a world-wide challenge with the aging of the population. In this work, novel supramolecular nanoagonists (NAs), constructed from alkaloids and phenolic acids, emerge as a carrier-free nanotherapy for efficacious osteoporosis treatment. These precision nanoagonists are formed through the self-assembly of berberine (BER) and chlorogenic acid (CGA), utilizing noncovalent electrostatic, π-π, and hydrophobic interactions. This assembly results in a 100% drug loading capacity and stable nanostructure. Furthermore, the resulting weights and proportions of CGA and BER within the NAs are meticulously controlled with strong consistency when the CGA/BER assembly feed ratio is altered from 1:1 to 1:4. As anticipated, our NAs themselves could passively target osteoporotic bone tissues following prolonged blood circulation, modulate Wnt signaling, regulate osteogenic differentiation, and ameliorate bone loss in ovariectomy-induced osteoporotic mice. We hope this work will open a new strategy to design efficient herbal-derived Wnt NAs for dealing with intractable osteoporosis.

Nanodiamond-based berberine aquasomes for enhancing penetration across epidermis to treat psoriasis.

The use of berberine hydrochloride (BCS class III) has limited application in psoriasis, when given as topical drug delivery systems, due to low permeability in the skin layer. Hence, berberine hydrochloride-loaded aquasome nanocarriers were developed for skin targeting, particularly epidermis (primary site of psoriasis pathophysiology) and enhance the skin permeability of berberine hydrochloride. Aquasomes were formulated using the adsorption method and characterized by structural morphology TEM, % drug adsorption, drug release profile (in-vitro and ex-vivo), in-vivo efficacy study and stability study. The reduced particle size and higher surface charge of SKF3 formulation (263.57 ± 27.78 nm and -21.0 ± 0.43 mV) showed improved stability of aquasomes because of the development of higher surface resistance to formation of aggregates. The adsorption of hydrophilic berberine and the non-lipidic nature of aquasomes resulted in % adsorption efficiency (%AE) of 94.46 ± 0.39 %. The controlled first-order release behavior of aquasomes was reported to be 52.647 ± 14.63 and 32.08 ± 12.78 % in in-vitro and ex-vivo studies, respectively. In-vivo studies demonstrated that topical application of berberine hydrochloride loaded aquasomes significantly alleviated psoriasis symptoms like hyperkeratosis, scaling and inflammation, due to the reduction in the inflammatory cytokines (IL-17 and IL-23). Therefore, aquasome formulation exhibits an innovative approach for targeted application of berberine hydrochloride in the management of psoriasis.

Lipids Extracted from Mycobacterial Membrane and Enveloped PLGA Nanoparticles for Encapsulating Antibacterial Drugs Elicit Synergistic Antimicrobial Response against Mycobacteria.

Tuberculosis (TB) is a chronic disease caused byMycobacterium tuberculosis (Mtb), which shows a long treatment cycle often leads to drug resistance, making treatment more difficult. Immunogens present in the pathogen's cell membrane can stimulate endogenous immune responses. Therefore, an effective lipid-based vaccine or drug delivery vehicle formulated from the pathogen's cell membrane can improve treatment outcomes. Herein, we extracted and characterized lipids fromMycobacterium smegmatis, and the extracts contained lipids belonging to numerous lipid classes and compounds typically found associated with mycobacteria. The extracted lipids were used to formulate biomimetic lipid reconstituted nanoparticles (LrNs) and LrNs-coated poly(lactic-co-glycolic acid) nanoparticles (PLGA-LrNs). Physiochemical characterization and results of morphology suggested that PLGA-LrNs exhibited enhanced stability compared with LrNs. And both of these two types of nanoparticles inhibited the growth of M. smegmatis. After loading different drugs, PLGA-LrNs containing berberine or coptisine strongly and synergistically prevented the growth of M. smegmatis. Altogether, the bacterial membrane lipids we extracted with antibacterial activity can be used as nanocarrier coating for synergistic antibacterial treatment of M. smegmatis─an alternative model of Mtb, which is expected as a novel therapeutic system for TB treatment.

Compound-compound interaction analysis of baicalin and berberine derivatives in aqueous solution.

Baicalin and berberine are biologically active constituents of the crude drugs Scutellaria root and Coptis rhizome/Phellodendron bark, respectively. Baicalin and berberine are reported to combine together as a 1:1 complex that forms yellow precipitates by electrostatic interaction in decoctions of Kampo formulae containing these crude drugs. However, the structural basis and mechanism for the precipitate formation of this compound-compound interaction in aqueous solution remains unclarified. Herein, we searched for berberine derivatives in the Coptis rhizome that interact with baicalin and identified the chemical structures involved in the precipitation formation. Precipitation assays showed that baicalin formed precipitates with berberine and coptisine but not with palmatine and epiberberine. Thus, the 2,3-methylenedioxy structure may be crucial to the formation of the precipitates, and electrostatic interaction is necessary but is not sufficient. In this multicomponent system experiment, palmatine formed a dissociable complex with baicalin and may competitively inhibit the formation of berberine and coptisine precipitation with baicalin. Therefore, the precipitation formed by berberine and baicalin was considered to be caused by the aggregation of the berberine-baicalin complex, and the 2,3-methylenedioxy structure is likely crucial to the aggregation of the complex.

Inhibition of inflammation by berberine: Molecular mechanism and network pharmacology analysis.

BACKGROUND: Traditional Chinese Medicine (TCM), renowned for its holistic approach with a 2000-year history of utilizing natural remedies, offers unique advantages in disease prevention and treatment. Berberine, found in various Chinese herbs, has been employed for many years, primarily for addressing conditions such as diarrhea and dysentery. Berberine has recently become a research focus owing to its pharmacological activities and benefits to human bodies. However, little is known about the anti-inflammatory mechanism of berberine. PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of berberine anti-inflammation and highlight and predict the potential therapeutic effects and systematic mechanism of berberine. METHODS: Recent studies (2013-2023) on the pharmacological effects and mechanisms of berberine anti-inflammation were retrieved from Web of Science, PubMed, Google Scholar, and Scopus up to July 2023 using relevant keywords. Network pharmacology and bioinformatics analysis were employed to predict the therapeutic effects and mechanisms of berberine against potential diseases. RESULTS: The related pharmacological mechanisms of berberine anti-inflammation include the inhibition of inflammatory cytokine production (e.g., IL-1ß, IL-6, TNF-α), thereby attenuating the inflammatory response; Inhibiting the activation of NF-κB signaling pathway and IκBα degradation; Inhibiting the activation of MAPK signaling pathway; Enhancing the activation of the STAT1 signaling pathway; Berberine interacts directly with cell membranes through a variety of pathways, thereby influencing cellular physiological activities. Berberine enhances human immunity and modulates immune system function, which is integral to addressing certain autoimmune and tumour-related health concerns. CONCLUSION: This study expounds on the correlation between berberine and inflammatory diseases, encapsulating the mechanisms through which berberine treats select typical inflammatory ailments. Furthermore, it delves into a deeper understanding of berberine's effectiveness by integrating network pharmacology and molecular docking techniques in the context of treating inflammatory diseases. It provides guidance and reference for berberine's subsequent revelation of the modern scientific connotation of Chinese medicine.

Berberine: Pharmacological Features in Health, Disease and Aging.

BACKGROUND: Berberine is the main active compound of different herbs and is defined as an isoquinoline quaternary botanical alkaloid found in barks and roots of numerous plants. It exhibits a wide range of pharmacological effects, such as anti-obesity and antidiabetic effects. Berberine has antibacterial activity against a variety of microbiota, including many bacterial species, protozoa, plasmodia, fungi, and trypanosomes. OBJECTIVE: This review describes the role of berberine and its metabolic effects. It also discusses how it plays a role in glucose metabolism, fat metabolism, weight loss, how it modulates the gut microbiota, and what are its antimicrobial properties along with its potential side effects with maximal tolerable dosage. METHODS: Representative studies were considered and analyzed from different scientific databases, including PubMed and Web of Science, for the years 1982-2022. RESULTS: Literature analysis shows that berberine affects many biochemical and pharmacological pathways that theoretically yield a positive effect on health and disease. Berberine exhibits neuroprotective properties in various neurodegenerative and neuropsychological ailments. Despite its low bioavailability after oral administration, berberine is a promising tool for several disorders. A possible hypothesis would be the modulation of the gut microbiome. While the evidence concerning the aging process in humans is more limited, preliminary studies have shown positive effects in several models. CONCLUSION: Berberine could serve as a potential candidate for the treatment of several diseases. Previous literature has provided a basis for scientists to establish clinical trials in humans. However, for obesity, the evidence appears to be sufficient for hands-on use.

Fluorimetric Cell Analysis with 9-Aryl-Substituted Berberine Derivatives as DNA-Targeting Fluorescent Probes.

DNA-sensitive fluorescent light-up probes based on berberine are presented. This biogenic fluorophore was chosen as central unit to use its potential biocompatibility and its DNA-binding properties. To provide predictable fluorescence quenching in aqueous solution and a fluorescence light-up effect upon DNA binding, aryl substituents were attached at the 9-position by Suzuki-Miyaura coupling reactions. The 9-arylberberine derivatives have a very low fluorescence quantum yield (Φfl =<0.02), which is caused by the radiationless deactivation of the excited state by torsional relaxation about the biaryl axis. In addition, these berberine derivatives intercalate into DNA with high affinity (Kb =2.0-22×104  M-1 ). Except for the nitrophenyl- and hydroxyphenyl-substituted derivatives, all tested compounds exhibited a pronounced fluorescence light-up effect upon association with DNA, because the deactivation of the excited-state by torsional relaxation is suppressed in the DNA binding site. Most notably, it was shown exemplarily with the 9-(4-methoxyphenyl)- and the 9-(6-methoxynaphthyl)-substituted derivatives that these properties are suited for fluorimetric cell analysis. In particular, these probes generated distinct staining patterns in eukaryotic cells (NIH 3T3 mouse fibroblasts), which enabled the identification of nuclear substructures, most likely heterochromatin or nucleoli, respectively.

The interaction on HSA and the antibacterial activity from four polyoxometalate hybrids based on berberine.

Four organic-polyoxometalate hybrids BR4[SiW12O40] (BR-SiW), BR3[PMo12O40] (BR-PMo), BR4K[EuSiW11O40]·2H2O (BR-EuSiW) and BR6Na3[EuW10O36] (BR-EuW) were fabricated by the polyoxometalates (POMs) anions and berberine cations (BR) noted for the alkaloids in traditional Chinese herbal medicine. These hybrids have been characterized and confirmed. The interaction between hybrids and human serum albumin (HSA) was investigated in a buffer solution (pH 7.4) using ultraviolet-visible light absorption and fluorescence techniques. The classical Stern-Volmer equation was used to analyze the fluorescence quenching at three temperatures (296, 303 and 310 K), and the static quenching mechanism for interaction was proposed. The Thermodynamic parameters, enthalpy, entropy change, and Gibbs free energy of hybrids interacting on HSA were calculated by Scatchard equation. The results indicated that therewas one binding site on the protein and BR-POMs all showed stronger binding force than that of raw materials. Synchronous fluorescence results showed that the binding sites of BR-POMs and HSA were not effectively affected the surrounding microenvironment. The following antibacterial experiments implied that inhibitory effect of hybrids were synergistic effect from organic active ingredient and POMs but the simple combination. All these data were prepared for further research on biology.

Evaluation of the size effect of hydrophobic ring substitution on 9-O position of berberine on DNA binding.

The interaction of deoxyribonucleic acid (DNA) with medicinally significant small molecules has long piqued the interest of researchers because its applications are directly related to the discovery of new classes of drugs. Keeping this in mind, here we report berberine derivatives and their interaction with calf thymus DNA (CT-DNA). In this report we discussed on the structural perspectives and thermodynamic characteristics of the interaction of four 9-O-substituted berberines (BRDR1 to BRDR4) with CT-DNA. The binding affinity of BRDR-DNA complexes increased with increasing the cycloalkane ring size of the substitution except BRDR2. The binding constant value obtained from UV-Visible spectral analysis was 1.12 × 106 for BRDR1, 0.37 × 106 for BRDR2, 1.72 × 106 for BRDR3 and 3.20 × 106 for BRDR4. Ferrocyanide quenching experiments revealed unequivocally that the analogues except BRDR2 had a partly intercalative binding to DNA. From the ITC experiment it was found that the bindings of BRDR1, BRDR3 and BRDR4 to DNA was favoured by negative enthalpy and positive entropy while BRDR2 was driven by positive enthalpy and positive entropy. In all cases the hydrophobic interaction plays a crucial role. Thus, the complete multispectroscopic and thermodynamic binding studies may be useful for new drug design and development.Communicated by Ramaswamy H. Sarma.

Chemical Characterization of the Precipitate Found in and Its Effect on Drug Release of the Scutellaria†baicalensis-Coptis†chinensis Extract.

Precipitate generation is a challenging issue during the production of herbal decoction as it affects the stability and bioavailability of active compounds. Here we explored the composition of the natural precipitate formed from and its effect on drug release of Scutellaria baicalensis-Coptis chinensis paired extract (SCPE). Furthermore, the surface morphology of the SCPE precipitate was also investigated. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was used to chemical component analysis and field emission scanning electron microscope (FE-SEM) was performed to particle observation. Baicalin (BA), berberine (BBR) and starch-arginine-rich polymers were abundant in the SCPE precipitate. FE-SEM micrographs showed spheroidal shaped particles in the SCPE supernatant, while spherical and porous tissue-shaped particles in the SCPE precipitate. In vitro drug release of baicalin and berberine contained in the precipitate may increase as the polymer is removed. The presence of polymer-related interactions were confirmed by the greater increase in solubility of baicalin upon addition of arginine and polymer. This was also supported by the solubility decrease of the BA-BBR complex in polymer solution and the gelation of the BA-BBR complex in arginine solution. Our results provide a scientific basis for elucidating the pharmaceutical properties of the decoction of S. baicalensis-C. chinensis-based herbal medicine.

Spray-dried Solid Lipid Nanoparticles for Enhancing Berberine Bioavailability via Oral Administration.

BACKGROUND: Berberine (BBR), an Eastern traditional medicine, has expressed novel therapeutic activities, especially for chronic diseases like diabetes, hyperlipemia, hypertension, and Alzheimer's disease. However, the low oral bioavailability of BBR has limited the applications of these treatments. Hence, BBRloaded solid lipid nanoparticles (BBR-SLNs) were prepared to improve BBR absorption into systemic circulations via this route. METHODS: BBR-loaded solid lipid nanoparticles (BBR-SLNs) were prepared by ultrasonication and then transformed into solid form via spray drying technique. The size morphology of BBR-SLNs was evaluated by dynamic light scattering (DLS) and scanning electron microscope (SEM). Crystallinity of BBR and interaction of BBR with other excipients were checked by spectroscopic methods. Entrapment efficiency of BBR-SLNs as well as BBR release in gastrointestinal conditions were also taken into account. Lastly, SLN's cytotoxicity for loading BBR was determined with human embryonic kidney cells (HEK293). RESULTS: Stearic acid (SA), glyceryl monostearate (GMS), and poloxamer 407 (P407) were selected for BBRSLNs fabrication. BBR-SLNs had homogenous particle sizes of less than 200 nm, high encapsulation efficiency of nearly 90% and loading capacity of above 12%. BBR-SLN powder could be redispersed without significant changes in physicochemical properties and was stable for 30 days. Spray-dried BBR-SLNs showed a better sustained in vitro release profile than BBR-SLNs suspension and BBR during the initial period, followed by complete dissolution of BBR over 24 hours. Notably, cell viability on HEK293 even increased up to 150% compared to the control sample at 100 µg/mL BBR-unloaded SLNs. CONCLUSION: Hence, SLNs may reveal a promising drug delivery system to broaden BBR treatment for oral administration.

Evaluation of berberine nanoparticles as a strategy to modulate acetylcholinesterase activity.

Researchers have concentrated efforts in the search for natural-based reversible inhibitors for cholinesterase enzymes as they may play a key role in the treatment of degenerative diseases. Diverse plant alkaloids can inhibit the action of acetylcholinesterase and, among them, berberine is a promising bioactive. However, berberine has poor water solubility and low bioavailability, which makes it difficult to use in treatment. The solid dispersion technique can improve the water affinity of hydrophobic substances, but berberine solid dispersions have not been extensively studied. Safety testing is also essential to ensure that the berberine-loaded solid dispersions are safe for use. This study investigated the effectiveness of berberine-loaded solid dispersions (SD) as inhibitors of acetylcholinesterase enzyme (AChE). Docking simulation was used to investigate the influence of berberine on AChE, and in vitro assays were conducted to confirm the enzymatic kinetics of AChE in the presence of berberine. Berberine SD also showed improved cytotoxic effects on tumoral cells when dispersed in aqueous media. In vivo assays using Allium cepa were implemented, and no cytotoxicity/genotoxicity was found for the berberine solid dispersion. These results suggest that berberine SD could be a significant step towards safe nanostructures for use in the treatment of neurodegenerative diseases.

Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye.

BACKGROUND: Dry eye disease (DED) is a multifactorial disease in ocular surface, and inflammation plays an etiological role. Berberine (BBR) has shown efficacy in treating inflammatory diseases. Yet, there was no adequate information related to the therapeutic effects of BBR for DED. PURPOSE: To detect the effects and explore the potential mechanisms of BBR on DED. STUDY DESIGN: In vitro, in vivo study and network pharmacology analysis were involved. METHOD: The human corneal epithelium cells viability was evaluated with different concentrations of BBR. Dry eye murine model was established by exposing to the desiccating stress, and Ciclosporin (CSA), BBR eye drops or vehicle were topical administration for 7 days. The phenol red cotton tests, Oregon-green-dextran staining and Periodic acid-Schiff staining were performed and evaluated the dry eye after treatment. Inflammation and apoptosis levels of ocular surface were quantified. The potential targets related to berberine and dry eye were collected from databases. The Protein-Protein interaction network analysis and GO & KEGG enrichment analysis were realized by STRING database, Metascape platform and Cytoscape software to find core targets and signaling pathways. The SchrÖdinger software was used to molecular docking and PyMOL software to visualization. Finally, the levels of PI3K/AKT/NFκB and MAPK pathways were detected. RESULT: The data revealed BBR could rescue impaired HCE under hyperosmotic conditions. In addition, BBR eye drops could ameliorate dry eye. And BBR eye drops suppressed the inflammatory factors and CD4+T cells infiltration in conjunctiva. Besides, BBR eye drops protected ocular surface by avoiding the severe apoptosis and decreasing the level of MMP-3 and MMP-9. 148 common targets intersection between BBR and dry eye were found via network pharmacology analysis. Core proteins and core pathways were identified through PPI and GO&KEGG enrichment analysis. Molecular docking displayed excellent binding between BBR and those core targets. Finally, in vivo study verified that BBR eye drops had a therapeutic effect in dry eye by inhibiting PI3K/AKT/NFκB and MAPK pathways. CONCLUSION: The research provided convincing evidence that BBR could be a candidate drug for dry eye.

Evaluation of calf thymus DNA binding of newly synthesize five 9 O Imidazolyl alkyl berberine derivative: A comparative multi-spectroscopic and calorimetric study.

DNA binding with small molecule plays an important role in the designing of various anticancer drugs with greater efficacy. The five 9-O-imidazolyl alkyl berberine derivatives (BI) of different chain length has been synthesized and fully characterized. The binding study of calf thymus DNA with these newly synthesized berberine derivative was performed using various biophysical techniques. The binding affinity of BI to calf thymus DNA increased with increasing the chain length. The binding constant value obtained from UV-Vis spectral analysis was 1.84x105for BI1, 2.01x105for BI2, 1.51 × 106 for BI3, 3.66 × 106 for BI4, 6.68 × 106. Partial intercalative binding with strong stabilization of the DNA helix was revealed from circular dichroism spectral study and viscosity measurement. From the ITC experiment it was revealed that the bindings of BI1, BI2, BI3, BI4 and BI5 to calf thymus DNA were favoured by a large positive favourable entropy and negative enthalpy change and the highest spontaneity found for BI5. With the increase in chain length the binding was driven by a stronger entropy term with a higher binding constant indicates involvement of hydrophobic force for all these interaction. High binding affinities of calf thymus DNA with berberine-imidazole derivatives might be helpful for new drug design.

Novel co-crystal of 3-methylcinnamic acid with berberine (1:1): synthesis, characterization, and intestinal absorption property.

OBJECTIVE: To synthesis a novel 'Pharmaceutical Cocrystal' of berberine (BBR) with coformer 3-methylcinnamic acid (3MCA) for increasing its solubility and intestinal absorption property. SIGNIFICANCE: BBR-HCl has poor liposolubility, difficulty in penetrating the cell membrane and absorption in the gastrointestinal tract, low bioavailability, and limited clinical application. A new cocrystal is formed by the interaction between 3-MCA and BBR through molecular interaction, which improves the physicochemical properties, intestinal absorption property, and hygroscopicity. METHODS: The solvent evaporation method was used to synthesize BCR-3MCA cocrystal. The physicochemical properties of the crystals were confirmed by different spectral techniques, i.e. by X-ray diffraction (PXRD, SXRD), thermogravimetry and differential thermal analysis (DSC, TGA), and scanning electron microscopy (SEM). Hygroscopicity of the cocrystal was evaluated by dynamic water vapor sorption (DVS). The intestinal absorption property was evaluated by the Ussing chamber system. RESULTS: BBR and 3MCA can be directly self-assembled into uniform co-crystal by hydrogen bonds and π-π stacking interactions. Compared with BBR-HCl, the solubility of BBR-3MCA cocrystal in polar solvents of water, methanol, ethanol, and isopropanol increased by 13.9, 1.5, 4.7, and 15.8 times, respectively. The apparent absorption and the absorption rate constants were increased by 7.7 and 5.6 times, respectively. Surprisingly, BBR-3MCA co-crystal almost had no hygroscopicity. CONCLUSION: The absolute molecular structure of the co-crystal was further confirmed by single crystal X-ray diffraction. The hydrogen bonds drove the formation of X-like one-dimensional unit. Compared to the BBR-HCl, BBR-3MCA cocrystal displayed superior dissolution and solubility performance, improved physical-chemical properties and significantly improved intestinal absorption.

Facile extraction of berberine from different plants, separation, and identification by thin-layer chromatography, high-performance liquid chromatography, and biological evaluation against Leishmaniosis.

The extraction of berberine was carried out from Berberis vulgaris, Berberis aquifolium, and Hydrastis canadensis plants using ethanol and water (70:30, v/v). The extracted berberine was characterized by ultraviolet-visible and Fourier-transform infrared spectroscopy. The purity of berberine was ascertained by thin-layer chromatography using n-propanol-formic acid-water (95:1:4) and (90:1:9) solvents. hRf values were in the range of 44-49 with compact spots (diameter 0.2-0.4 cm). HPLC was carried out using ammonium acetate buffer and acetonitrile in gradient mode with Zodiac (4.6 × 150 mm, 3 µm) column. The flow rate was 1.0 mL/min and detection was at 220 nm. The values of separation and resolution factors of the standard and the extracted berberine were in the range of 1.13-1.16 and 1.40-1.71, respectively. A comparison has shown that both thin-layer chromatography and high-performance liquid chromatography (HPLC) methods found applications in different situations and requirements. The extracted berberine samples were used to treat Leishmaniosis and the results showed better activity of berberine in comparison to the standard drug Amphotericin B. Briefly, the reported research is a novel and may be used to extract berberine from plants, separation and identification of berberine by thin layer chromatography and HPLC and to treat Leishmaniosis.

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.

Insight on Structural Modification, Cytotoxic or Anti-Proliferative Activity, Structure-Activity Relationship of Berberine Derivatives.

Berberine (BBR) is a quaternary ammonium alkaloid isolated from the Traditional Chinese Medicine Coptis chinensis. It possesses a plethora of pharmacological activities because its unique structure properties make it readily interact with macromolecules through π-π stacking and electrostatic interaction. Its anti-tumor effects are receiving more and more attention in recent years. Cytotoxicity and anti-proliferation are the important anti-tumor modes of BBR, which have been studied by many research groups. This study aims to review the structural modifications of BBR and its cytotoxic derivatives. Also, to study the corresponding structure-activity relationship. BBR showed potential activities toward tumor cells, however, its modest activity and poor physicochemical properties hindered its application in clinical. Structural modification is a common and effective approach to improve BBR's cytotoxic or anti-proliferative activities. The structural modifications of BBR, the cytotoxic or anti-proliferative activities of its derivatives, and the corresponding structure-activity relationship (SAR) were summarized in the review. The concluded SAR of BBR derivatives with their cytotoxic or anti-proliferative activities will provide great prospects for the future anti-tumor drug design with BBR as the lead compound.

Binding of berberine derivates to G-quadruplex: insight from a computational study.

Human telomerase exhibits significant activity in cancer cells relative to normal cells, which contributes to the immortal proliferation of cancer cells. To counter this, the stabilization of G-quadruplexes formed in the guanine-rich sequence of the cancer cell chromosome has emerged as a promising avenue for anti-cancer therapy. Berberine (BER), an alkaloid that is derived from traditional Chinese medicines, has shown potential for stabilizing G-quadruplexes. To investigate the atomic interactions between G-quadruplexes and BER and its derivatives, molecular dynamics simulations were conducted. Modeling the interactions between G-quadruplexes and ligands accurately is challenging due to the strong negative charge of nucleic acids. Thus, various force fields and charge models for the G-quadruplex and ligands were tested to obtain precise simulation results. The binding energies were calculated by a combination of molecular mechanics/generalized Born surface area and interaction entropy methods, and the calculated results correlated well with experimental results. B-factor and hydrogen bond analyses demonstrated that the G-quadruplex was more stable in the presence of ligands than in the absence of ligands. Calculation of the binding free energy showed that the BER derivatives bind to a G-quadruplex with higher affinity than that of BER. The breakdown of the binding free energy to per-nucleotide energies suggested that the first G-tetrad played a primary role in binding. Additionally, energy and geometric properties analyses indicated that van der Waals interactions were the most favorable interactions between the derivatives and the G-quadruplexes. Overall, these findings provide crucial atomic-level insights into the binding of G-quadruplexes and their inhibitors.

Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations.

INTRODUCTION: Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats. AREAS COVERED: Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed. EXPERT OPINION: Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.