Quaternary Benzylisoquinoline Alkaloids Research Articles

Preparation of Berberine Chloride Nanoparticles by Ball Milling Method

Berberine is a quaternary benzylisoquinoline alkaloid that has been used for the local treatment of gastrointestinal tract diseases. Recently, several pharmacological effects of berberine have been reported, which include anti-hypertension, antitumor, anti-hypercholesterolemia, and neuroprotective effects. However, berberine has exhibited poor aqueous solubility and low oral bioavailability. To overcome these limitations, this study aims to develop and investigate nano berberine. Nano berberine fabricated by ball milling method is a simple process and easily applied in the production scale. The characterization of nano berberine was evaluated, including appearance, particle size, potential zeta, dissolution in vitro in a phosphate buffer media (pH 6.8), differential scanning calorimetry (DSC) analysis, fourier transformed infrared spectroscopy (FTIR), and X-ray diffraction analysis (XRD). Results from this study showed that spray-dried nano berberine powder was almost uniform in size, particle size average of 570.7 nm, and potential zeta of -28.6 mV. The dissolution in vitro study revealed that nano berberine was about 2 times more soluble than raw berberine for 60 minutes. No incompatibility between drug and excipients can be observed through FTIR and DSC analysis. XRD analysis suggested that raw berberine and nano berberine might exist in a crystal form. Thus, findings from this study indicate that the physicochemical properties of spray-dried nano berberine may increase the bioavailability of oral berberine.

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review.

Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed.

Promising Antioxidative Effect of Berberine in Cardiovascular Diseases.

Berberine (BBR), an important quaternary benzylisoquinoline alkaloid, has been used in Chinese traditional medicine for over 3,000 years. BBR has been shown in both traditional and modern medicine to have a wide range of pharmacological actions, including hypoglycemic, hypolipidemic, anti-obesity, hepatoprotective, anti-inflammatory, and antioxidant activities. The unregulated reaction chain induced by oxidative stress as a crucial mechanism result in myocardial damage, which is involved in the pathogenesis and progression of many cardiovascular diseases (CVDs). Numerous researches have established that BBR protects myocardium and may be beneficial in the treatment of CVDs. Given that the pivotal role of oxidative stress in CVDs, the pharmacological effects of BBR in the treatment and/or management of CVDs have strongly attracted the attention of scholars. Therefore, this review sums up the prevention and treatment mechanisms of BBR in CVDs from in vitro, in vivo, and finally to the clinical field trials timely. We summarized the antioxidant stress of BBR in the management of coronary atherosclerosis and myocardial ischemia/reperfusion; it also analyzes the pathogenesis of oxidative stress in arrhythmia and heart failure and the therapeutic effects of BBR. In short, BBR is a hopeful drug candidate for the treatment of CVDs, which can intervene in the process of CVDs from multiple angles and different aspects. Therefore, if we want to apply it to the clinic on a large scale, more comprehensive, intensive, and detailed researches are needed to be carried out to clarify the molecular mechanism and targets of BBR.

Bioavailability of berberine: challenges and solutions

Berberine is a quaternary benzylisoquinoline alkaloid with multiple pharmacological effects used for the treatment of hypertension, tumors, bacterial infections, inflammation, HIV, and cardiac diseases. In phase I clinical trials, berberine is safe at excessive doses but manifests poor bioavailability. Major challenges like poor absorption, rapid metabolism, and rapid systemic elimination are responsible for low plasma and tissue levels of berberine. Various strategies have been undertaken by several researchers to overcome this issue and enhance the bioavailability of berberine. This includes the design of new formulation strategies; novel drug delivery systems (NDDS) like liposomes, nanosized dosage forms, phospholipid complexes, mucoadhesive microparticles, and micoemulsions; the use of adjuvants; and the design of structural analogous of berberine. This review focuses on the occurrence of berberine in numerous plants and its pharmacological activities as evidenced through numerous preclinical and clinical studies. The later part of this review highlights the bioavailability issue of berberine which arises due to its poor absorption, elevated rate and extent of metabolism, and quick elimination and clearance from the body. A systematic effort has beenmade to analyze the various formulation strategies, including the design of newer berberine analogues and derivatives. These strategies can be further explored to increase the bioavailability, medicinal value, and application of this promising molecule.

Berberine mitigates oxidative damage associated with testicular impairment following mercury chloride intoxication.

In this study, we assessed the protective effect of berberine (BBR) against mercuric chloride (HgCl2)-induced reproductive impairment. Twenty-eight adult male Wistar albino rats were placed into four equal groups: control, BBR, HgCl2, and BBR+HgCl2. All the treatments were orally administered for seven consecutive days. The rats exposed to HgCl2 showed a marked decrease in testosterone accompanied by an increase in lipid peroxidation (LPO) and nitric oxide (NO). Additionally, HgCl2 decreased glutathione (GSH) content, deactivated catalase (CAT) and glutathione reductase (GR), and suppressed the activities and mRNA expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the testicular tissue. In addition, histological deformations and testicular cell loss were recorded, as evidenced by the upregulation of caspase-3 following HgCl2 intoxication. Notably, BBR administration reversed the testicular impairments associated with HgCl2 exposure. These findings suggest that BBR protected the testicular tissue following HgCl2 exposure through inhibiting the disturbance in the testosterone level and enhanced the antioxidant capacity. PRACTICAL APPLICATIONS: Heavy metals are naturally existing metallic elements in the earth's crust. These trace metals have the potential to cause multiple adverse reactions to the living systems, even at low exposure doses. Human exposure may also result from industrial, agricultural, and domestic activities. Berberine (BBR, a naturally occurring quaternary benzylisoquinoline alkaloid) is a protoberberine and is the representative main active ingredient in all parts of Berberis species. BBR has been used widely in folk medicine worldwide for its multiple pharmacological and therapeutic activities; for example, in the treatment of digestive and reproductive system disorders, microorganism infections, hemorrhage and wound healing, and cardiovascular and ophthalmic diseases. We found that BBR administration was able to abrogate significantly the reproductive toxicity associated with Hg intoxication. This protective effect comes from its strong antioxidant, anti-inflammatory, and antiapoptotic activities; suggesting that BBR may be applied to alleviate reproductive toxicity associated with Hg intoxication.

Bioassay-directed isolation of quaternary benzylisoquinolines from Berberis integerrima with bactericidal activity against Brucella abortus.

Berberis integerrima Bonge. (Syn: Berberis densiflora Boiss. & Buhse) is a shrub widely distributed in Middle East and central part of Asia. An ethnobotanical study revealed that indigenous and tribal people in Iran use B. integerrima root decoction for treatment of brucellosis. Therefore, the aim of this study was bioassay directed isolation of antibacterial compounds from this plant based on their in vitro bactericidal activity against Brucella abortus. Briefly, the ethanol extract of B. integerrima was fractioned and subjected to preliminary antibacterial screening tests against Brucella. The more active fraction (Fr.3) was subjected to purification by repeated chromatography systems. Quaternary benzylisoquinoline alkaloids including columbamine, palmatine, berberine, and jatrorhizine were four main components identified in the selected active fraction. Except for berberine which is reported before, palmatine, columbamine and jatrorhizine are isolated for the first time from this plant. Anti-brucellosis properties of isolated compounds 1-4 were studied against B. abortus under different test conditions. In minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) results, jatrorhizine (4) showed more antibacterial activity with MIC and MBC of 0.78 and 1.56 μg/mL, respectively. In both agar well diffusion and disk diffusion ANOVA results showed that there were statistically significant differences between compounds 1-4 versus placebo in all of the tested concentration (P <0.001). In conclusion, all of four alkaloids showed potent antibacterial activity against B. abortus but jatrorhizine and columbamine with free hydroxyl group on C-3 or C-2 showed more activity than palmatine and berberine without any free hydroxyl group on their structures. The antibacterial effects of columbamine (15 μg/mL) and jatrorhizine (15 μg/mL) were comparative to streptomycin (10 μg/mL) as standard drug which candidate them for more pharmacological researches to find new antibacterial agents against brucellosis.

Binding of berberine to a membrane fraction from Coptis cells

3H-Labelled berberine, a quaternary benzylisoquinoline alkaloid, was shown to bind specifically to a microsomal fraction prepared from cultured cells of Coptis japonica capable of accumulating the alkaloid in the vacuole. The Scatchard plot of the data suggested the existence of a single berberine-binding site with a dissociation constant ( K d) of 1.67 μM for berberine. The binding of [ 3H]berberine to the membrane fraction was reversible, the optimum pH for binding being between 9 and 10. An addition of either coptisine or jatrorrhizine, which are congeners of berberine, to the assay mixture significantly decreased [ 3H] berberine-binding, indicating that the binding is highly specific for protoberberine-type alkaloids indigenous to the C. japonica. An SH-blocking reagent, iodoacetate, as well as an excess amount of inorganic cation almost completely inhibited the binding. Further fractionation of the microsomes by sucrose density-gradient centrifugation suggested that the binding site was not associated with plasma membrane, endoplasmic reticulum or tonoplast, but with an unidentified membrane (ϱ = 1.08–1.10 g cm −3), which might be involved in the transport of berberine to the vacuole.

Kinetics of alkaloid uptake by cultured cells of Coptis japonica

Cultured cells of Coptis japonica (Ranunculaceae) were shown to take up exogenously added, quaternary benzylisoquinoline alkaloids of the protoberb