RESUMO
The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals.
Assuntos
Berberina , Compostos de Bifenilo , Colite Ulcerativa , Lignanas , Nanoestruturas , Animais , Colite Ulcerativa/tratamento farmacológico , Berberina/química , Berberina/farmacologia , Berberina/uso terapêutico , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Camundongos , Compostos de Bifenilo/química , Nanoestruturas/química , Masculino , Sulfato de Dextrana/química , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Disponibilidade BiológicaRESUMO
Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine's physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure-activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.
Assuntos
Berberina , Berberina/química , Berberina/farmacologia , Berberina/análogos & derivados , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese químicaRESUMO
Berberine hydrochloride (BBR), used in various traditional medicinal practices, has a variety of pharmacological effects. It is a plant-derived quaternary isoquinoline alkaloid with a low water solubility and can be used in the treatment of various conditions. However, the therapeutic use of BBR has been compromised because of its hydrophobic characteristics, in addition to its low stability and poor bioavailability. To overcome these drawbacks of BBR's oral bioavailability, technologies like liposomal delivery systems have been developed to ensure enhanced absorption. But conventional liposomes have low physical and chemical stability due to delicate liposomal membranes, peroxidation and rapid clearance from the bloodstream. Surface modification of liposomes could be a solution and creating a liposome with plant-based fibers as surface material will provide enhanced stability, aqueous solubility and protection against degradation. Consequently, the aim of this study is to create and describe a Fiber Interlaced Liposome™ (FIL) as a vehicle for an enhanced bioavailability platform for BBR and other biomolecules. This optimised FIL-BBR formulation was analysed for its structural and surface morphological characteristics by using FTIR, SEM, TEM, XRD, zeta potential and DSC. Encapsulation efficiency, stability, and sustained release studies using an in vitro digestion model with simulated gastric and intestinal fluids were also examined. FIL formulation showed a sustained release of BBR at 59.03 % as compared to the unformulated control (46.73 %) after 8 h of dialysis. Furthermore, the FIL-BBR demonstrated enhanced stability in the simulated gastric fluid (SGF) in addition to a more sustained release in the simulated intestinal fluid (SIF). The efficacy of FIL-BBR were further anlaysed by an in vivo bioavailability study using male Wistar rats and it demonstrated a 3.37-fold higher relative oral bioavailability compared to the unformulated BBR. The AUC 0-t for BBR in FIL-BBR was 1.38 ng.h/mL, significantly greater than the unformulated BBR (0.41 ng.h/mL). Similarly, the Cmax for BBR in FIL-BBR (50.98 ng/mL) was discovered to be far greater than unformulated BBR (15.54 ng/mL) after the oral administration. These findings imply that fruit fiber based liposomal encapsulation improves the stability and slows down BBR release, which could be advantageous for applications requiring a higher bioavailability and a more sustained release.
Assuntos
Berberina , Disponibilidade Biológica , Lipossomos , Solubilidade , Berberina/administração & dosagem , Berberina/farmacocinética , Berberina/química , Animais , Ratos , Masculino , Ratos Wistar , Administração Oral , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Composição de Medicamentos/métodos , Química Farmacêutica/métodosRESUMO
Wound healing represents a complex biological process crucial for tissue repair and regeneration. In recent years, biomaterial-based scaffolds loaded with bioactive compounds have emerged as promising therapeutic strategies to accelerate wound healing. In this study, we investigated the properties and wound healing effects of cryogels loaded with calcium peroxide (CP) and berberine (BB). The cryogels were synthesized through a cryogenic freezing technique and displayed pore diameters of 83 ± 39 µm, with porosity exceeding 90%. Following 20 days of degradation, the percentage of remaining weight for GPC and GPC-CP-BB cryogels was determined to be 12.42 ± 2.45% and 10.78 ± 2.08%, respectively. Moreover, the swelling ratios after 3 minutes for GPC and GPC-CP-BB were found to be 22.10 ± 0.05 and 21.00 ± 0.07, respectively. In vitro investigations demonstrated the cytocompatibility of the cryogels, with sufficient adhesion and proliferation of fibroblast (NIH-3T3) cells observed on the scaffolds, along with their hemocompatibility. Furthermore, the cryogels exhibited sustained release kinetics of both calcium peroxide and berberine, ensuring prolonged therapeutic effects at the wound site. In vivo assessment using a rat model of full-thickness skin wounds demonstrated accelerated wound closure rates in animals treated with the GPC-CP-BB scaffold compared to controls. Histological analysis revealed enhanced granulation tissue formation, re-epithelialization, and collagen deposition in the GPC-CP-BB group. Overall, our findings suggest that the scaffold loaded with CP and BB holds great promise as a therapeutic approach for promoting wound healing. Its multifaceted properties offer a multifunctional platform for localized delivery of therapeutic agents while providing mechanical support and maintaining a favorable microenvironment for tissue regeneration.
Assuntos
Berberina , Criogéis , Peróxidos , Cicatrização , Berberina/química , Berberina/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Criogéis/química , Camundongos , Ratos , Células NIH 3T3 , Peróxidos/química , Peróxidos/farmacologia , Proliferação de Células/efeitos dos fármacos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Ratos Sprague-Dawley , Masculino , PorosidadeRESUMO
BACKGROUND: Wound healing pivots on a finely orchestrated inflammatory cascade, critical for tissue repair. Chronic wounds, compounded by persistent inflammation and susceptibility to infection, pose formidable clinical challenges. Nanofiber dressings offer promising avenues for wound care, yet their interaction with inflammation and infection remains elusive. We aim to delineate the inflammatory cascade preceding wound closure and assess Cu@Bbc nanofibers' therapeutic efficacy in mitigating inflammation and combating infection. Their unique attributes suggest promise in modulating inflammation, fostering tissue regeneration, and preventing microbial colonization. Investigating the intricate interplay between nanofiber scaffolds, inflammation, and infection may unveil mechanisms of enhanced wound healing. Our findings could stimulate the development of tailored dressings, urgently needed for effective wound management amidst immune dysregulation, infection, and inflammation. METHODS: In this investigation, we synthesized Cu@Bbc nanofibers, incorporating curcumin and berberine chloride, for wound healing applications. We evaluated their individual and combined antibacterial, anti-biofilm, and antioxidant activities, alongside binding affinity with pro-inflammatory cytokines through molecular docking. Morphological characterization was conducted via SEM, FTIR assessed functional groups, and wettability contact angle measured hydrophobic properties. The physical properties, including tensile strength, swelling behavior, and thermal stability, were evaluated using tensile testing, saline immersion method and thermogravimetric analysis. Biodegradability of the nanofibers was assessed through a soil burial test. Biocompatibility was determined via MTT assay, while wound healing efficacy was assessed with in vitro scratch assays. Controlled drug release and antibacterial activity against MRSA were examined, with in vivo assessment in a zebrafish model elucidating inflammatory responses and tissue remodeling. RESULTS: In this study, the synergistic action of curcumin and berberine chloride exhibited potent antibacterial efficacy against MRSA, with significant anti-mature biofilm disruption. Additionally, the combination demonstrated heightened antioxidant potential. Molecular docking studies revealed strong binding affinity with pro-inflammatory cytokines, suggesting a role in expediting the inflammatory response crucial for wound healing. Morphological analysis confirmed nanofiber quality, with drug presence verified via FTIR spectroscopy. Cu@Bbc demonstrated higher tensile strength, optimal swelling behavior, and robust thermal stability as evaluated through tensile testing and thermogravimetric analysis. Additionally, the Cu@Bbc nanofiber showed enhanced biodegradability, as confirmed by the soil burial test. Biocompatibility assessments showed favorable compatibility, while in vitro studies demonstrated potent antibacterial activity. In vivo zebrafish experiments revealed accelerated wound closure, re-epithelialization, and heightened immune response, indicative of enhanced wound healing. CONCLUSION: In summary, our investigation highlights the efficacy of Cu@Bbc nanofibers, laden with curcumin and berberine chloride, in displaying robust antibacterial and antioxidant attributes while also modulating immune responses and inflammatory cascades essential for wound healing. These results signify their potential as multifaceted wound dressings for clinical implementation.
Assuntos
Antibacterianos , Berberina , Curcumina , Staphylococcus aureus Resistente à Meticilina , Nanofibras , Infecções Estafilocócicas , Cicatrização , Peixe-Zebra , Animais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Curcumina/farmacologia , Curcumina/química , Curcumina/uso terapêutico , Berberina/farmacologia , Berberina/química , Berberina/uso terapêutico , Cicatrização/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Nanofibras/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Sinergismo Farmacológico , Simulação de Acoplamento Molecular , Citocinas/metabolismo , Biofilmes/efeitos dos fármacos , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity (KD approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI-binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures under physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is an excellent EPI binder with a KD of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.
Assuntos
Berberina , Quadruplex G , Berberina/química , Berberina/análogos & derivados , Berberina/farmacologia , Humanos , DNA/química , Ácidos Nucleicos Peptídicos/químicaRESUMO
The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.
Assuntos
Antineoplásicos , Berberina , Curcumina , Limoninas , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana , Espectrometria de Fluorescência , Humanos , Berberina/farmacologia , Berberina/química , Berberina/metabolismo , Curcumina/farmacologia , Curcumina/metabolismo , Curcumina/química , Limoninas/farmacologia , Limoninas/química , Limoninas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Albumina Sérica Humana/metabolismo , Albumina Sérica Humana/química , Sítios de Ligação , Termodinâmica , Linhagem Celular Tumoral , Dicroísmo CircularRESUMO
Bovine mastitis caused by infectious pathogens, mainly Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), constitutes a major destructive challenge for the dairy industry and public health. Berberine chloride (BER) and Cyperus rotundus possess a broad spectrum of anti-inflammatory, antioxidant, antibacterial, and antiproliferative activities; however, their bioavailability is low. This research aimed first to prepare an ethanolic extract of Cyperus rotundus rhizomes (CRE) followed by screening its phytochemical contents, then synthesis of BER and CRE loaded chitosan nanoparticles (NPs) (BER/CH-NPs and CRE/CH-NPs), afterward, the analysis of their loading efficiency in addition to the morphological and physicochemical characterization of the formulated NPs employing Scanning Electron Microscopy (SEM), Zeta Potential (ZP), Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD) assessments compared to their crude forms to evaluate the enhancement of bioavailability and stability. Isolation of bacterial strains from the milk of mastitic cows, used for induction of mammary gland (MG) inflammation in female albino rats, and a preliminary investigation of the prophylactic oral doses of the prepared NPs against S. aureus-induced mastitis in female rats. The minimal inhibitory concentration (MIC) of BER/CH-NPs and CRE/CH-NPs is 1 mg/kg b.w. BER/CH-NPs and CRE/CH-NPs alone or in combination show significant (P ≤ 0.05) DPPH radical scavenging activity (69.2, 88.5, and 98.2%, respectively) in vitro. Oral administration of BER/CH-NPs and CRE/CH-NPs to mastitis rats significantly (P ≤ 0.05) attenuated TNF-α (22.1, 28.6 pg/ml), IL-6 (33.4, 42.9 pg/ml), IL-18 (21.7, 34.7 pg/ml), IL-4 (432.9, 421.6 pg/ml), and MPO (87.1, 89.3 pg/ml) compared to mastitis group alongside the improvement of MG histopathological findings without any side effect on renal and hepatic functions. Despite promising results with BER and CRE nanoparticles, the study is limited by small-scale trials, a focus on acute administration, and partially explored nanoparticle-biological interactions, with no economic or scalability assessments. Future research should address these limitations by expanding trial scopes, exploring interactions further, extending study durations, and assessing economic and practical scalability. Field trials and regulatory compliance are also necessary to ensure practical application and safety in the dairy industry. In conclusion, the in vitro and in vivo results proved the antioxidant and anti-inflammatory efficacy of BER/CH-NPs and CRE/CH-NPs in low doses with minimal damage to the liver and kidney functions, supposing their promising uses in mastitis treatment.
Assuntos
Anti-Inflamatórios , Antioxidantes , Berberina , Cyperus , Mastite , Nanopartículas , Extratos Vegetais , Animais , Feminino , Cyperus/química , Ratos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antioxidantes/farmacologia , Antioxidantes/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Berberina/farmacologia , Berberina/química , Berberina/administração & dosagem , Bovinos , Nanopartículas/química , Mastite/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Mastite Bovina/tratamento farmacológico , Mastite Bovina/microbiologia , Escherichia coli/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Quitosana/química , Quitosana/farmacologiaRESUMO
Efficiently mining and identification of new compounds from the extensive MS/MS datasets of plant extracts poses a significant challenge due to the structural diversity and compositional complexity inherent in natural products (NPs). Various data post-processing techniques have been developed to simplify the interpretation of MS/MS data; however, they often suffer from limited specificity and precision. Meanwhile, structure annotation following data post-processing is particularly time-consuming. In this study, we introduced an innovative strategy named MS-SMART, which integrates three intelligent algorithms: automatic mining of diagnostic ions, rapid filtration of alkaloids from untargeted MS/MS data, and structural recommendations for filtered components. The feasibility of this approach for rapidly discovering novel compounds was demonstrated using berberine-type alkaloids as an example. Firstly, diagnostic ions were automatically extracted and validated using available reference data. Subsequently, berberine-type compounds were filtered from raw MS/MS data. Finally, the structures of the target components were recommended using building blocks derived from berberines reported in various plants. A total of 103, 198, 60, 80 and 51 berberines were efficiently identified in diverse families and genera, including Stephaniae Epigaeae Radix, Coptidis Rhizoma, Phellodendri Chinensis Cortex, Phellodendri Amurensis Cortex and Corydalis Decumbentis Rhizoma, with 99, 169, 50, 64 and 40 new compounds identified, respectively. Among these, 8, 14, 8, 7 and 12 berberines were confirmed by reference compounds. This strategy provides a new research paradigm for the rapid discovery and identification of different types of new compounds in complex samples.
Assuntos
Algoritmos , Produtos Biológicos , Mineração de Dados , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Produtos Biológicos/química , Produtos Biológicos/análise , Berberina/química , Berberina/análise , Extratos Vegetais/química , Alcaloides/análise , Alcaloides/químicaRESUMO
An advanced biodegradable packaging film with antimicrobial and fresh-maintaining functions was constructed by incorporating berberine and L-arginine into the starch/polyvinyl alcohol (PVA) film matrix. The film was endowed with a dual antibacterial capacity thanks to the intrinsic antibacterial capability of berberine and cascaded photodynamic sterilization. The aggregated berberine presents an excellent photodynamic activity to generate reactive oxygen species (ROS), which further triggers the NO release from L-arginine. Under the synergetic action of ROS and NO, the as-prepared film not only has an antibacterial efficiency of over 99 % against both S. aureus and E. coli but also delays fruit ripening through antagonistic effects on ethylene to extend the shelf life of food. Meanwhile, the as-prepared film presents UV-shielding properties, thermal stability, and considerable mechanical properties. Specifically, the packaging film exhibits good biocompatibility and is biodegradable, with a degradation rate of 56 % within 16 days, which has great potential for improving food safety and environmental events.
Assuntos
Embalagem de Alimentos , Conservação de Alimentos , Álcool de Polivinil , Amido , Esterilização , Álcool de Polivinil/química , Amido/química , Conservação de Alimentos/métodos , Esterilização/métodos , Embalagem de Alimentos/métodos , Antibacterianos/farmacologia , Antibacterianos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Berberina/química , Berberina/farmacologiaRESUMO
We investigated the binding between the c-MYC G-quadruplex (GQ) and berberine chloride (BCl) in an aqueous two-phase system (ATPS) with 12.3 wt % polyethylene glycol and 5.6 wt % dextran, mimicking the highly crowded intracellular biomolecular condensates formed via liquid-liquid phase separation. We found that in the ATPS, complex formation is significantly altered, leading to an increase in affinity and a change in the stoichiometry of the complex with respect to neat buffer conditions. Thermodynamic studies reveal that binding becomes more thermodynamically favorable in the ATPS due to entropic effects, as the strong excluded volume effect inside ATPS droplets reduces the entropic penalty associated with binding. Finally, the binding affinity of BCl for the c-MYC GQ is higher than those for other DNA structures, indicating potential specific interactions. Overall, these findings will be helpful in the design of potential drugs targeting the c-MYC GQ structures in cancer-related biocondensates.
Assuntos
Berberina , Quadruplex G , Proteínas Proto-Oncogênicas c-myc , Berberina/química , Dextranos/química , DNA/química , Polietilenoglicóis/química , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Termodinâmica , Água/químicaRESUMO
Berberine (BBR), as a natural isoquinoline alkaloid, has demonstrated various pharmacological activities, and is widely applied in the treatment of diseases. The quantitative analysis of BBR is important for pharmacological studies and clinical applications. In this work, utilizing the specific interaction between BBR and triplex DNA, a sensitive and selective fluorescent detecting method was established with DNA-templated silver nanoclusters (DNA-AgNCs). After binding with the triplex structure in the template of DNA-AgNCs, BBR quenched the fluorescence of DNA-AgNCs and formed BBR-triplex complex with yellow-green fluorescence. The ratiometric fluorescence signal showed a linear relationship with BBR concentration in a range from 10 nM to 1000 nM, with a detection limit of 10 nM. Our method exhibited excellent sensitivity and selectivity, and was further applied in BBR detection in real samples.
Assuntos
Berberina , DNA , Nanopartículas Metálicas , Prata , Espectrometria de Fluorescência , Berberina/química , Berberina/análise , Prata/química , Nanopartículas Metálicas/química , DNA/química , DNA/análise , Espectrometria de Fluorescência/métodos , Fluorescência , Limite de Detecção , HumanosRESUMO
Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery. Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. Nano-delivery systems increase drug concentration at the tumor site by improving pharmacological activity and tissue distribution, enhancing drug bioavailability. Organic nanocarriers have advantages for berberine delivery including biocompatibility, encapsulation, and controlled release of the drug. While the advantages of inorganic nanocarriers for berberine delivery mainly lie in their efficient loading ability of the drug and their slow release ability of the drug. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery.
Assuntos
Berberina , Neoplasias , Berberina/química , Berberina/farmacocinética , Berberina/farmacologia , Berberina/administração & dosagem , Humanos , Neoplasias/tratamento farmacológico , Animais , Portadores de Fármacos/química , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Sistemas de Liberação de Fármacos por Nanopartículas/química , Nanomedicina , Nanotecnologia/métodos , Sistemas de Liberação de Medicamentos/métodosRESUMO
PURPOSE: The present work seeks to develop, assess and refine a nanoethosomal vaginal in situ gel containing Berberine, aimed at enhancing its efficacy in treating Poly Cystic Ovary Syndrome (PCOS). This formulation aims to augment drug permeation, enable controlled release kinetics, and mitigate oral adverse effects commonly associated with Berberine administration. METHOD: Nanoethosomes formulated using diverse soya lecithin-ethanol concentrations within a 32 full-factorial-design, sought optimal formulations based on particle size and %entrapment-efficiency. Subsequent scrutiny involved PDI, Zeta potential and drug-content evaluation. TEM analysis authenticated morphology, while in vitro drug release from Nanoethosomes was examined. Pluronic F-127 concentrations (16%-21%w/v) were explored for the in situ gel, analyzing pH, gelation time and gelation temperature. The refined gel underwent evaluations for viscosity and in vitro diffusion. In vivo assessment covered pharmacokinetics, vaginal irritancy and Mifepristone-induced PCOS management, validated through histopathological and biochemical analysis, juxtaposing findings across normal, diseased, plain Berberine gel and standard metformin administered groups. RESULTS: Optimized Nanoethosomal Formulation(F3) displayed particle size of 183.5 nm, 82.58 % as %entrapment-efficiency, PDI of 0.137, -50.34 mV as zeta potential and 81.64 ± 1.57 % drug-content. TEM analysis confirmed spherical, nano-sized particles. In vitro studies exhibited 80.45 % drug release over 24 h. The formulated gel with 18 % Pluronic F-127 showed viscosity ranging from 193.01 ± 0.16cps to 1817.08 ± 1.67cps with temperature changes from 25 ± 2.0 °C to 38 ± 2.0 °C. In vitro diffusion revealed 85.99 %drug release from optimized gel. In vivo animal studies demonstrated increased plasma drug concentration, non-irritating properties in vaginal tests, and efficacy in managing Mifepristone-induced PCOS compared to other treatments. Short-term stability evaluations confirmed thermodynamic stability at room-temperature.
Assuntos
Berberina , Liberação Controlada de Fármacos , Síndrome do Ovário Policístico , Ratos Wistar , Cremes, Espumas e Géis Vaginais , Feminino , Animais , Berberina/administração & dosagem , Berberina/farmacocinética , Berberina/química , Berberina/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Cremes, Espumas e Géis Vaginais/química , Cremes, Espumas e Géis Vaginais/administração & dosagem , Vagina/efeitos dos fármacos , Vagina/patologia , Tamanho da Partícula , Ratos , Administração Intravaginal , Poloxâmero/química , Nanopartículas/química , Metformina/administração & dosagem , Metformina/farmacocinética , Metformina/química , ViscosidadeRESUMO
Berberine bridge enzyme-like oxidases are often involved in natural product biosynthesis and are seen as essential enzymes for the generation of intricate pharmacophores. These oxidases have the ability to transfer a hydride atom to the FAD cofactor, which enables complex substrate modifications and rearrangements including (intramolecular) cyclizations, carbon-carbon bond formations, and nucleophilic additions. Despite the diverse range of activities, the mechanistic details of these reactions often remain incompletely understood. In this Review, we delve into the complexity that BBE-like oxidases from bacteria, fungal, and plant origins exhibit by providing an overview of the shared catalytic features and emphasizing the different reactivities. We propose four generalized modes of action by which BBE-like oxidases enable the synthesis of natural products, ranging from the classic alcohol oxidation reactions to less common amine and amide oxidation reactions. Exploring the mechanisms utilized by nature to produce its vast array of natural products is a subject of considerable interest and can lead to the discovery of unique biochemical activities.
Assuntos
Produtos Biológicos , Oxirredutases , Produtos Biológicos/metabolismo , Produtos Biológicos/química , Oxirredutases/metabolismo , Oxirredutases/química , Flavoproteínas/metabolismo , Flavoproteínas/química , Oxirredução , Berberina/metabolismo , Berberina/química , Bactérias/enzimologia , Bactérias/metabolismo , Fungos/enzimologia , Plantas/enzimologia , Plantas/metabolismoRESUMO
Bacterial infections pose a substantial threat to human health, particularly with the emergence of antibiotic-resistant strains. Therefore, it is essential to develop novel approaches for the efficient treatment of bacterial diseases. This study presents a therapeutic approach involving BBR@MMT nanosheets (NSs), wherein montmorillonite (MMT) was loaded with berberine (BBR) through an ion intercalation reaction to sterilize and promote wound healing. BBR@MMT exhibits nano-enzymatic-like catalytic activity, is easy to synthesize, and requires low reaction conditions. This nanocomplex showed photodynamic properties and superoxide dismutase (SOD) activity. The in vitro experiments indicated that BBR@MMT was able to effectively inhibit the growth of Gram-positive bacteria (S. aureus) and Gram-negative bacteria (E. coli) through the production of ROS when exposed to white light. Meanwhile, BBR@MMT inhibited the secretion of pro-inflammatory factors and scavenged free radicals via its SOD-like activity. In vivo results showed that BBR@MMT NSs were capable of effectively promoting the wound-healing process in infected mice under white light irradiation. Hence, it can be concluded that photodynamic therapy based on BBR@MMT NSs with nano-enzymatic activity has the potential to be used in treating infections and tissue repair associated with drug-resistant microorganisms.
Assuntos
Antibacterianos , Bentonita , Berberina , Escherichia coli , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Cicatrização , Bentonita/química , Bentonita/farmacologia , Berberina/farmacologia , Berberina/química , Cicatrização/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Animais , Escherichia coli/efeitos dos fármacos , Camundongos , Staphylococcus aureus/efeitos dos fármacos , Fotoquimioterapia , Nanoestruturas/química , Tamanho da Partícula , Propriedades de Superfície , Humanos , Luz , Espécies Reativas de Oxigênio/metabolismoRESUMO
Staphylococcus aureus is characterized by its high resistance to conventional antibiotics, particularly methicillin-resistant (MRSA) strains, making it a predominant pathogen in acute and chronic wound infections. The persistence of acute S. aureus wound infections poses a threat by increasing the incidence of their chronicity. This study investigated the potential of photodynamic activation using phytochemical-antibiotic combinations to eliminate S. aureus under conditions representative of acute wound infections, aiming to mitigate the risk of chronicity. The strategy applied takes advantage of the promising antibacterial and photosensitising properties of phytochemicals, and their ability to act as antibiotic adjuvants. The antibacterial activity of selected phytochemicals (berberine, curcumin, farnesol, gallic acid, and quercetin; 6.25-1000 µg/mL) and antibiotics (ciprofloxacin, tetracycline, fusidic acid, oxacillin, gentamicin, mupirocin, methicillin, and tobramycin; 0.0625-1024 µg/mL) was screened individually and in combination against two S. aureus clinical strains (methicillin-resistant and -susceptible-MRSA and MSSA). The photodynamic activity of the phytochemicals was assessed using a light-emitting diode (LED) system with blue (420 nm) or UV-A (365 nm) variants, at 30 mW/cm2 (light doses of 9, 18, 27 J/cm2) and 5.5 mW/cm2 (light doses of 1.5, 3.3 and 5.0 J/cm2), respectively. Notably, all phytochemicals restored antibiotic activity, with 9 and 13 combinations exhibiting potentiating effects on MSSA and MRSA, respectively. Photodynamic activation with blue light (420 nm) resulted in an 8- to 80-fold reduction in the bactericidal concentration of berberine against MSSA and MRSA, while curcumin caused 80-fold reduction for both strains at the light dose of 18 J/cm2. Berberine and curcumin-antibiotic combinations when subjected to photodynamic activation (420 nm light, 10 min, 18 J/cm2) reduced S. aureus culturability by ≈9 log CFU/mL. These combinations lowered the bactericidal concentration of antibiotics, achieving a 2048-fold reduction for gentamicin and 512-fold reduction for tobramycin. Overall, the dual approach involving antimicrobial photodynamic inactivation and selected phytochemical-antibiotic combinations demonstrated a synergistic effect, drastically reducing the culturability of S. aureus and restoring the activity of gentamicin and tobramycin.
Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Fármacos Fotossensibilizantes , Compostos Fitoquímicos , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos da radiação , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Curcumina/farmacologia , Curcumina/química , Ácido Gálico/química , Ácido Gálico/farmacologia , Berberina/farmacologia , Berberina/química , Luz , Fotoquimioterapia , Infecções Estafilocócicas/tratamento farmacológico , Quercetina/farmacologia , Quercetina/química , HumanosRESUMO
Thirty protoberberine derivatives, of which twenty five were new, were synthesized and evaluated for their anti-Helicobacter pylori (HP) activities, taking 2,3,10-trimethoxy-9-p-methylbenzylaminoprotopalmatine chloride 1 as the lead. Among them, berberine (BBR) derivative 7c displayed the highest potency against six tested metronidazole (MTZ)-resistant strains and two tested MTZ-susceptible strains with the MIC values of 0.4-1.6 µg/mL with favorable druglike profiles including low toxicity and high stabilities in plasma and artificial gastric fluid. Mechanistic study revealed that 7c might target HP urease with IC50 value of 0.27 µg/mL against Jack bean urease. Furthermore, 7c might change the permeability of the bacterial membrane and direct interact with HP DNA, which also contribute to its bactericidal activity. Therefore, BBR derivatives constituted a new family of anti-HP candidates, with the advantage of good safety profile and multi-target mechanisms, and are worthy for further investigation.
Assuntos
Antibacterianos , Berberina , Helicobacter pylori , Testes de Sensibilidade Microbiana , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Berberina/farmacologia , Berberina/química , Berberina/análogos & derivados , Berberina/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Descoberta de Drogas , Relação Dose-Resposta a Droga , Urease/antagonistas & inibidores , Urease/metabolismo , HumanosRESUMO
BACKGROUND: Berberine (BBR), the main active component of Coptis chinensis Franch., has a variety of pharmacological effects, notably anti-inflammatory, which make it a potential treatment for ulcerative colitis (UC). Nevertheless, the specific target and the mode of action of BBR against UC are still unclear. PURPOSE: Here, we aim to identify BBR's anti-inflammatory target and its mode of action in UC treatment. METHODS: The therapeutic effects of BBR and Coptis chinensis Franch. extract were first assessed in UC mice. Then, stable isotope labeling using amino acids in cell culture-activity-based protein profiling (SILAC-ABPP) was applied to identify the anti-inflammatory target proteins of BBR in an inflammation model of RAW264.7 cells stimulated by LPS. Molecular docking, drug affinity responsive target stability (DARTS), molecular dynamics simulation, cellular thermal shift assay (CETSA), and biological layer interference (BLI) measurement were employed to study the interaction between BBR and its targets. Lentiviral transfection was used to knock down the target protein and investigate BBR's anti-inflammatory mechanism. RESULTS: BBR and Coptis chinensis Franch. extracts both significantly alleviated UC in mice. SILAC-ABPP identified IRGM1 as BBR's anti-inflammatory target, with its overexpression reduced by BBR treatment in both RAW264.7 cell inflammation models stimulated by LPS and UC mice. BBR significantly reduced inflammatory cytokines in LPS-induced RAW264.7 cells by blocking the PI3K/AKT/mTOR pathway. Knockdown of IRGM1 weakened BBR's effects on cytokine expression and pathway regulation. CONCLUSION: For the first time, IRGM1 was identified as the direct anti-inflammatory target of BBR. BBR has the potential to inhibit IRGM1 expression in vitro as well as in vivo. The molecular mechanism of BBR's anti-inflammatory activity was inhibiting the PI3K/AKT/mTOR pathway by targeting IRGM1.
Assuntos
Anti-Inflamatórios , Berberina , Colite Ulcerativa , Coptis , Proteínas de Ligação ao GTP , Animais , Camundongos , Berberina/farmacologia , Berberina/química , Colite Ulcerativa/tratamento farmacológico , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Masculino , Proteínas de Ligação ao GTP/metabolismo , Coptis/química , Simulação de Acoplamento Molecular , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas c-akt/metabolismo , Extratos Vegetais/farmacologia , Serina-Treonina Quinases TOR/metabolismo , LipopolissacarídeosRESUMO
CONTEXT: Diabetes mellitus (DM) is a metabolic disorder disease that causes hyperglycemia conditions and associated with various chronic complications leading to mortality. Due to high toxicity of conventional diabetic drugs, the exploration of natural compounds as alternative diabetes treatments has been widely carried out. Previous in silico studies have highlighted berberine, a natural compound, as a promising alternative in antidiabetic therapy, potentially acting through various pathways, including the inhibition of the FOXO1 transcription factor in the gluconeogenesis pathway. However, the specific mechanism by which berberine interacts with FOXO1 remains unclear, and research in this area is relatively limited. Therefore, this study aims to determine the stability of berberine structure with FOXO1 based on RMSD, RMSF, binding energy, and trajectory analysis to determine the potential of berberine to inhibit the gluconeogenesis pathway. This research was conducted by in silico method with molecular docking using AutoDock4.2 and molecular dynamics study using Amber20, then visualized by VMD. METHODS: Docking between ligand and FOXO1 receptor was carried out with Autodock4.2. For molecular dynamics simulations, the force fields of DNA.OL15, protein.ff14SB, gaff2, and tip3p were used.