Quaternary Isoquinoline Alkaloids Research Articles

Preparation, characterization, in vitro and in vivo studies of liposomal berberine using novel natural Fiber Interlaced Liposomal technology

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.

Characterization and Pharmacokinetic Assessment of a New Berberine Formulation with Enhanced Absorption In Vitro and in Human Volunteers.

Berberine is a plant-origin quaternary isoquinoline alkaloid with a vast array of biological activities, including antioxidant and blood-glucose- and blood-lipid-lowering effects. However, its therapeutic potential is largely limited by its poor oral bioavailability. The aim of this study was to investigate the in vitro solubility and Caco-2 cell permeability followed by pharmacokinetic profiling in healthy volunteers of a new food-grade berberine delivery system (i.e., Berberine LipoMicel®). X-ray diffractometry (XRD), in vitro solubility, and Caco-2 cell permeability indicated higher bioavailability of LipoMicel Berberine (LMB) compared to the standard formulation. Increased aqueous solubility (up to 1.4-fold), as well as improved Caco-2 cell permeability of LMB (7.18 × 10-5 ± 7.89 × 10-6 cm/s), were observed when compared to standard/unformulated berberine (4.93 × 10-6 ± 4.28 × 10-7 cm/s). Demonstrating better uptake, LMB achieved significant increases in AUC0-24 and Cmax compared to the standard formulation (AUC: 78.2 ± 14.4 ng h/mL vs. 13.4 ± 1.97 ng h/mL, respectively; p < 0.05; Cmax: 15.8 ± 2.6 ng/mL vs. 1.67 ± 0.41 ng/mL) in a pilot study of healthy volunteers (n = 10). No adverse reactions were reported during the study period. In conclusion, LMB presents a highly bioavailable formula with superior absorption (up to six-fold) compared to standard berberine formulation and may, therefore, have the potential to improve the therapeutic efficacy of berberine. The study has been registered on ClinicalTrials.gov with Identifier NCT05370261.

ANDALIMAN QUERCETIN (ZANTHOXYLUM ACANTHOPODIUM DC.) USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) METHOD AND ITS ANTIFUNGAL ACTIVITY AGAINST PITYROSPORUM OVALE

People today complain with dandruff accompanied by itching will cause a lack of confidence because of the unpleasant smell and reduce the beauty of the hair. Andaliman is a plant that grows a lot in the Toba Samosir area which is usually used as a spice for cooking. Examination of secondary metabolite compounds contained in these natural materials is the main thing that is important to do. In other studies, andaliman has been studied to provide antimicrobial, antioxidant, and anti-inflammatory effects.&#x0D; The test method is carried out using the High Performance Liquid Chromatography (HPLC) Method and the minimum inhibitory concentration test using the diffusion method in order to use paper backups with several variations in test concentration.&#x0D; This is related to the content of secondary metabolites such as flavonoids, terpene alkaloids, benzophenthridine alkaloids, pyranoquinoline alkaloids, quaternary isoquinoline alkaloids, aporphyrine alkaloids, essential oils and several types of lignin. Flavonoids are secondary metabolites of polyphenols found in many plants and have a variety of biological effects including antiviral, anti-inflammatory, and antioxidant. Quercetin to derivative active compounds&#x0D; The test results of the minimum inhibitory concentration of the extract showed an average inhibitory power of 17.26 mm at a concentration of 80% and EEAD quercetin levels with a concentration of 6.25; 12,5; 25; 50; and 100 ?g/ml contains quercetin percentages of 143.5, 242.15, 395.12, 865.2, and 1134.12 ?g/ml.

Studies on synthesis, physicochemical properties, biological activities of two novel berberine-based salts with DL-mandelate and cinnamate anions

Berberine (BBR) is a natural quaternary isoquinoline alkaloid which is derived from the traditional Chinese medicine Coptis chinensis and exerts various pharmacological effects. However, low solubility in water has greatly limited its clinical application. This study prepared two novel berberine-based salts (berberine DL-mandelate ([BBR][MAN]) and berberine cinnamate ([BBR][CIN])) to improve the physicochemical properties and bioavailability of berberine. Many techniques, like 1H and 13C NMR, FTIR, ESI-MS, and thermogravimetric analyzes were utilized to characterize two salts. The solubility and octanol/water partition coefficient in water and simulated body fluids (simulated body, simulated intestinal and simulated gastric fluids) were determined. Self-aggregation behaviors of two salts in water have been investigated by conductometry at different temperatures. The obtained critical aggregation concentration (cac) was used for the calculation of various thermodynamic properties namely standard Gibbs energy change (ΔGm0), enthalpy change (ΔHm0), and entropy change (ΔSm0) in the aggregation progress. The volumetric properties including the infinite dilution apparent molar volumes (V2,φ0), infinite dilution apparent molar expansibility (Eφ0) and thermal expansion coefficient (β) for [BBR][MAN] were also determined to study its solvation behavior in aqueous solution. In addition, the antibacterial effect of two salts on three strains (Staphylococcus aureus, Bacillus subtilis and Candida albicans) was measured, and the minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values were obtained. The results show that [BBR][MAN] has better antibacterial effect than [BBR][CIN]. The esterase-like activity assay demonstrated a decrease in enzyme activity of BSA in presence of two berberine-based salts. Cytotoxicity evaluation shows that two salts have potent in vitro anticancer activities against B16-F10 cancer cell lines.

Inhibitory Activity of Quaternary Isoquinoline Alkaloids on Soluble Epoxide Hydrolase.

The quaternary isoquinoline alkaloids of palmatine (1), berberine (2), and jatrorrhizine (3) were evaluated in terms of their ability to inhibit soluble epoxide hydrolase (sEH). They had similar inhibitory activities, with IC50 values of 29.6 ± 0.5, 33.4 ± 0.8, and 27.3 ± 0.4 μM, respectively. Their respective Ki values of 26.9, 46.8, and 44.5 μM—determined by enzyme kinetics—indicated that they inhibited the catalytic reaction by binding noncompetitively with sEH. The application of computational chemistry to the in vitro results revealed the site of the receptor to which the ligand would likely bind. Accordingly, three alkaloids were identified as having a suitable basic skeleton for lead compound development of sEH inhibitors.

Novel berberine-based pharmaceutical salts with fatty acid anions: Synthesis, characterization, physicochemical properties

Berberine (BBR), a quaternary isoquinoline alkaloid found in a Chinese herb medicine from Berberis species plants, was utilized to synthesize three new biocompatible berberine-based pharmaceutical salts, featuring three mid-chain fatty acid anions derived from animal and vegetable oils. Three salts [BBR][FA] were namely berberine caproate [BBR][CAP], berberine heptylate [BBR][HEP] and berberine octoate [BBR][OCT]. These compounds were characterized using 1H and 13C NMR, FTIR, ESI-MS, and thermogravimetric analyses. The solubility and octanol/water partition coefficient were evaluated in water and simulated body fluids (simulated gastric, simulated intestinal and simulated body fluids). The water solubility of [BBR][FA] was higher than that of salt precursor berberine chloride [BBR][Cl]. The minimum inhibitory concentration and minimum bactericidal or fungicidal concentration against three strains (Staphylococcus aureus, Bacillus subtilis and Candida albicans) were also examined. The results showed that they have similar antimicrobial activity to [BBR][Cl]. Furthermore, transport and volumetric properties (density and conductivity) were determined to investigate their aggregation and solvation behaviors in aqueous solution. The limiting molar conductivity, Ʌ0, critical micelle concentration, cmc, apparent molar volume at infinite dilution, V2,φ0, the apparent molar expansibility at infinite dilution, Eφ0, etc for [BBR][FA] were calculated. Effect of the length in alkyl chain of fatty acid anions in [BBR][FA] and temperature on the obtained properties as well as the nature of the interactions in aqueous [BBR][FA] solutions have been discussed.

Improvement of anticancer effect of berberine by salt formation modifications

BackgroundBerberine is a quaternary isoquinoline alkaloid that possesses a significant therapeutic effect on a variety of cancers. However, due to poor bioavailability, an increased dose is often required to achieve therapeutic goals. To improve the activities of natural berberine, most modifications were focused on the positive isoquinoline unit by grafting long aliphatic chains or heterocycles. However, the negative part is ignored. At this point, the strategy of salt formation modifications with short- and medium-chain fatty acids was proposed in this article. PurposeUsing salt modification to enhance the antitumor activity of berberine and explore the mechanism. MethodsFour short- and medium-chain fatty acid salts of berberine were prepared from berberine hydrochloride by salt formation modification with the sodium salt of butyric, caproic, octanoic, and decanoic acid, respectively. The cytotoxicity of four berberine salts on B16-F10, A549, HepG2, and U373 cancer cell lines was explored. Through cell localization, Mitochondrial membrane potential assay, and Western blotting analysis explored the mechanism of berberine salt-induced apoptosis. Its anticancer activity in vivo was demonstrated by the mouse xenograft model. ResultsThe four berberine fatty acid salts exhibited an enhanced inhibitory effect on B16-F10, A549, HepG2, and U373 cancer cell lines, particularly on B16-F10 cells. Meanwhile, the four berberine fatty acid salts can inhibit the migration of B16-F10 cells. The four berberine fatty acid salts induce cancer cell apoptosis through the mitochondrial pathway, which was confirmed by the mitochondrial colocalization, the decreased mitochondrial membrane potential as well as activation of caspase-3, cytochrome C (Cyt-C), and down-regulated expression of B-cell lymphoma 2 (Bcl-2). Most importantly, the four berberine fatty acid salts inhibited tumor growth in the in vivo B16-F10 melanoma model without generating side effects intraperitoneally. ConclusionsThis study revealed that salt formation modification may be an effective strategy to optimize the anticancer property of berberine hydrochloride and demonstrated the four berberine fatty acid salts induced apoptosis through the mitochondrial apoptotic pathway.

Design, synthesis and mechanism study of novel natural-derived isoquinoline derivatives as antifungal agents.

In screening for natural fungicidal leads, two series of novel 3-aryl-isoquinoline derivatives 8 and 9 were designed and synthesized based on sanguinarine, chelerythrine and berberine. Their structures were confirmed by 1D, 2D NMR and HRMS. Most of the title compounds showed medium to excellent antifungal activity in vitro at 50mg/L, which were much more active than the lead of sanguinarine. Especially, 9f possessed the best effective against Alternaria solani (80.4%), Alternaria alternata (88.2%) and Physalospora piricola (93.8%). Furthermore, the EC50 of 9f (3.651mg/L) against P. piricola was marginally better than chlorothalonil (3.869mg/L). In vivo antifungal activity of 9f against P. piricola was studied on apples. The curative and protection results at the dosage of 50 and 100mg/L showed as 70.45 ~ 81.67% and 64.96 ~ 80.34%, respectively, which were equal to that of chlorothalonil (80.30 ~ 86.67%, 73.08 ~ 76.92%). Molecular electrostatic potential and molecular docking analysis revealed that 9f was fully covered by positive potential contour, which was easier to interact with the negative amino acid resides of succinate dehydrogenase than 8f. 9f could be used as a novel antifungal lead compound for further study. Two series of novel isoquinoline derivatives 8, 9 containing 3-aryl were rational designed and synthesized based on quaternary isoquinoline alkaloids. The bioassay and interaction mechanism studies indicated that 9f should be considered as potential antifungal lead.

Some of South Sumatran Plants Containing Alkaloids

A phytochemical survey for alkaloid-containing plants has been conducted in South Sumatra including traditional medicinal plants. During the survey 180 satisfactory herbarium sample were obtained and all of them were tested for alkaloids. The results showed that 33 species gave a positive test for alkaloids, and high alkaloid contents were shown by: Alstonia scholaris, Alstonia angustiloba, Ervatamia coronariaa, Voacanga foetida Bl. K. Schum, Litseaacceden toides K &amp; V, Litsea angualata, Litsea tomentosa, Fibraurea chloroleuca Miers (root), and Uncaria cordata (Lour.) Merr. The aboved survey was also continued to be an intensively phytochemical work focusing on alkaloid of Fibraurea chloroleuca Miers root. A quaternary isoquinoline alkaloid as a yellowish crystal, m.p. 214-215 oC; MS (FAB) m/z 352 has been successfully isolated and tested for antibacterial activity. This isolated alkaloid significantly inhibited Bacilus substilis, Shigela dysentriae, Staphylococus aireus, and Pseudomonas sp growth at 1 mg/mL. As a result, all of these alkaloid-containing plants are potential to explore their alkaloids and utilitarian for traditional medicines.

Discovery and structural optimization of 9-O-phenylsulfonyl-berberines as new lipid-lowering agents

Berberine is a quaternary isoquinoline alkaloid that exhibits potent hypoglycemic and hypolipidemic activity. Many medicinal chemists are currently working on structural modifications around the parent scaffold of berberine, expecting to further enhance its hypolipidemic activity and reducing its cytotoxicity. In this study, a focused berberine-like compound library containing 12,600 molecules was built via the introduction of various “drug-like” fragments at the C8 and C9 positions of berberine. Sixteen comopounds were hit by using the in-house QSAR models previously reported by our group. Considering synthesis feasibility and the cost of building-blocks, only four berberine analogs (library ID: 2028, 3847, 6033, and 12456) were selected and synthesized for investigating their lipid-lowering activities. Preliminary lipid-lowering study showed that compound 12456 with the phenylsulfonyl group at the C9 position had potent cholesterol inhibitory activity in HepG2 cells, superior to that of the parent compound berberine. Subsequently, a total of twenty-five 9-O-phenylsulfonyl-berberines (1a-1y) and twenty-four 9-O-phenylsulfonyl-tetrahydroberberine (2a-2x) were designed, synthesized, and evaluated by lipid-lowering experiments. The results displayed that most compounds exhibited more lipid-lowering activities than berberine. Among them, compound 1m inhibited cholesterol production close to 50% in both cell models when compared with the blank control; the inhibition of triglycerides exceeded 70%. Moreover, 1m also had significant pharmacological effects on the inhibition of LDLC and promotion of HDLC production, especially in the HepG2 cell model, in which the inhibitory rate against LDLC was close to 70% and the increase rate of HDLC was more than 75%. The hypolipidemic experiment of SD rats demonstrated that after 40 days of administration (1m, 15 mg/kg/d), blood cholesterol was reduced by 19.6%, triglycerides reduced by 34.52%, and LDLC reduced by 41.49%, when compared with the high-fat diet model (HFD). In addition, after 80 days of administration, the three indexes of 1m were still better than that of berberine. Oil Red O staining and H&E staining results showed that 1m exhibited potent lipid scavenging activity. All in all, 1m was discovered and identified as a potent lipid-lowering agent and a new berberine-like candidate, being evaluated by subsequent studies.

Berberine-loaded liposomes for oral delivery: Preparation, physicochemical characterization and in-vivo evaluation in an endogenous hyperlipidemic animal model

Berberine (BBR) is a plant-origin quaternary isoquinoline alkaloid presenting exogenous cholesterol lowering and anti-hyperlipidemia therapeutic effects. The aim of this study was to design and generate BBR-loaded proliposomes (PLs) as solid templates for high-dose liposomes and consequently, to enhance the oral bioavailability and therapeutic effect of BBR. An air-suspension coating (layering) method was used for generating BBR-loaded PLs. The size, distribution size, morphology, and entrapment efficiency (EE) of the final reconstituted liposomes were assessed. The oral bioavailability and endogenous cholesterol lowering effects of BBR loaded in liposomes were investigated in rats and mice, respectively. The BBR-loaded PLs showed a smooth BBR-embedded film around micron-scale carrier particles (mannitol). The reconstituted BBR-loaded liposomes had a nano-scale average size (116.6 ± 5.8 nm), narrow size distribution (polydispersity index, PDI 0.269 ± 0.038), and high EE (87.8 ± 1.0%). The oral bioavailability of reconstituted BBR-loaded liposomes at a dose of 100 mg/kg in rats was increased even 628% compared to that obtained with pure BBR (according to 90% confidence interval). The BBR-loaded liposomes at the daily oral dose 100 mg/kg in P-407- reduced total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic mice by 15.8%, 38.2%, and 57.0%, respectively.

Nanoformulation and Evaluation of Oral Berberine-Loaded Liposomes.

Berberine (BBR) is a poorly water-soluble quaternary isoquinoline alkaloid of plant origin with potential uses in the drug therapy of hypercholesterolemia. To tackle the limitations associated with the oral therapeutic use of BBR (such as a first-pass metabolism and poor absorption), BBR-loaded liposomes were fabricated by ethanol-injection and thin-film hydration methods. The size and size distribution, polydispersity index (PDI), solid-state properties, entrapment efficiency (EE) and in vitro drug release of liposomes were investigated. The BBR-loaded liposomes prepared by ethanol-injection and thin-film hydration methods presented an average liposome size ranging from 50 nm to 244 nm and from 111 nm to 449 nm, respectively. The PDI values for the liposomes were less than 0.3, suggesting a narrow size distribution. The EE of liposomes ranged from 56% to 92%. Poorly water-soluble BBR was found to accumulate in the bi-layered phospholipid membrane of the liposomes prepared by the thin-film hydration method. The BBR-loaded liposomes generated by both nanofabrication methods presented extended drug release behavior in vitro. In conclusion, both ethanol-injection and thin-film hydration nanofabrication methods are feasible for generating BBR-loaded oral liposomes with a uniform size, high EE and modified drug release behavior in vitro.

Berberine Mediated CD47-Blocking As a Potential Immunotherapy in Diffuse Large B-Cell Lymphoma

Keywords diffuse large B-cell lymphoma; CD47; berberine; immunotherapy; macrophage Introduction Cluster of differentiation 47 (CD47) is a tetraspanin that expresses widely in human tissue and overexpresses in several malignance cells. The interaction between CD47 overexpressing on tumor cells and signal regulatory protein alpha (SIRP-α) on macrophages triggers an inhibitory signal cascade that suppresses the phagocytosis function. Berberine is a quaternary amine isoquinoline alkaloid which is traditionally used in intestinal infection and found to have anti-tumor activities in several tumors. However, the function and mechanism of berberine in immunoregulation targeting CD47 is undefined. Herein, we investigated the functional significance of CD47 in diffuse large B-cell lymphoma (DLBCL) progression and proposed an adjuvant agent for DLBCL treatment. Methods Paraffin imbedding tissue sections of 45 newly diagnosed DLBCL patients and 25 reactive hyperplasia (RHL) patients were obtained after informed consents. CD47 expression profile was analyzed in DLBCL sections and DLBCL cell lines. CD68, a biomarker of macrophages, was stained in DLBCL sections and the number of CD68 positive macrophages per high power field (HPF) was counted. The phagocytosis suppressing function of CD47 was detected in a co-culture system of macrophages induced from peripheral blood mononuclear cells (PBMCs) with DLBCL cells pretreated with RNAi-mediated CD47 knockdown lentivirus or anti-CD47 antibody (clone B6H12). CD47 level was analyzed after berberine treatment, and related regulatory pathway was explored. Results Firstly, we analyzed the CD47 expression in tissue sections form DLBCL and RHL patients (Figure 1A). Compared to RHL, CD47 was overexpressed in DLBCL tissues (31/45 vs 10/25, p=0.016, Figure 1B). CD47 overexpression was correlation with higher Ann-Arbor stage(p=0.028), but not with age, gender, NCCN-IPI score, serum LDH and DLBCL subtype. CD68 positive macrophages infiltration was detected in DLBCL tissue sections (Figure 1C, red arrow), and CD47 overexpression was correlation with higher macrophages infiltration (Figure 1D). Further, aberrantly increased expression of CD47 was also detected in some DLBCL cell lines (Figure 1E-F). Interestingly, total CD47 protein level was detected to be overexpressed in LY3 and Val cells, however, no statistical significance was found when the cytomembrane CD47 level was compared. To investigate the biofunction of CD47 in DLBCL, expression of CD47 was down-regulated by RNAi-mediated knockdown lentivirus in LY1 cells. ShCD47 or shNC LY1 cells was co-cultured with PBMC-derived macrophages, and the phagocytosis ratio was significantly elevated in shCD47 cells (Figure 2A). Consistently, the anti-phagocytosis effect of CD47 was also proved by blocking CD47 on LY1 cells via anti-CD47 antibody (clone B6H12) in the co-culture system (Figure 2B). To validate the impact of berberine on CD47 expression, DLBCL cells were treated with 30μM berberine for 0, 24 and 48 hours. The results revealed that CD47 was downregulated by berberine at a time-dependent manner (Figure 3A and B). To explore the upstream of CD47 in DLBCL, inhibitors of CD47-related upstream protein were applied to LY1 cells. The results showed that inhibition of ERK1/2 phosphorylation and c-Myc expression could suppress CD47 expression (Figure 3C). The expression level of c-Myc and p-ERK1/2 was also decreased after berberine treatment, which was consistent with the downregulation of CD47, indicating that berberine restrained CD47 expression through the ERK/c-Myc pathway (Figure 3D). Engulfment of LY1 cells by macrophages was improved when LY1 cells were pretreated with 30μM berberine for 48 hours (Figure 3E). Combination of berberine and B6H12 showed a more potent enhancement of macrophage function than single agent (Figure 3F). Moreover, rituximab-mediated phagocytosis was observed and proved to be synergized by berberine (Figure 3G). Conclusion Our results highlighted that CD47 was a significant feature and played an anti-phagocytosis function in DLBCL progression. We provided evidence for the first time that berberine could enhance rituximab-mediated phagocytosis and restore macrophage function in tumor microenvironment via suppressing CD47 expression, which provided novel insights into the rituximab based immunochemotherapy and CD47-targeted therapy in DLBCL. Disclosures No relevant conflicts of interest to declare.

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

Berberine (BER)—an anti-inflammatory quaternary isoquinoline alkaloid extracted from plants—has been reported to have a variety of biologic properties, including antileishmanial activity. This work addresses the preparation of BER-loaded liposomes with the aim to prevent its rapid liver metabolism and improve the drug selective delivery to the infected organs in visceral leishmaniasis (VL). BER liposomes (LP-BER) displayed a mean size of 120 nm, negative Z-potential of −38 mV and loaded 6 nmol/μmol lipid. In vitro, the loading of BER in liposomes enhanced its selectivity index more than 7-fold by decreasing its cytotoxicity to macrophages. In mice, LP-BER enhanced drug accumulation in the liver and the spleen. Consequently, the liposomal delivery of the drug reduced parasite burden in the liver and spleen by three and one logarithms (99.2 and 93.5%), whereas the free drug only decreased the infection in the liver by 1-log. The organ drug concentrations—far from IC50 values— indicate that BER immunomodulatory activity or drug metabolites also contribute to the efficacy. Although LP-BER decreased 10-fold—an extremely rapid clearance of the free drug in mice—the value remains very high. Moreover, LP-BER reduced plasma triglycerides levels.

The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches.

Berberine is a quaternary isoquinoline alkaloid that has been isolated from numerous plants which are still in use today as medicine and herbal supplements. The great deal of enthusiasm for intense research on berberine to date is based on its diverse pharmacological effects via action on multiple biological targets. Its poor bioavailability resulting from low intestinal absorption coupled with its efflux by the action of P-glycoprotein is, however, the major limitation. In this communication, the chemical approach of improving berberine’s bioavailability and pharmacological efficacy is scrutinised with specific reference to type-2 diabetes and associated diseases such as hyperlipidaemia and obesity. The application of modern delivery systems, research from combination studies to preparation of berberine structural hybrids with known biologically active compounds (antidiabetic, antihyperlipidaemic and antioxidant), as well as synthesis approaches of berberine derivative are presented. Improvement of bioavailability and efficacy through in vitro and ex vivo transport studies, as well as animal models of bioavailability/efficacy in lipid metabolism and diabetes targets are discussed.

Development and Percutaneous Permeation Study of Escinosomes, Escin-Based Nanovesicles Loaded with Berberine Chloride.

Escin is a natural saponin, clinically used for the anti-edematous and anti-inflammatory effects. The aim of the study was to explore the possibility of converting escin into vesicle bilayer-forming component. The hyaluronidase inhibition activity of escin was evaluated after its formulation in escinosomes. Berberine chloride, a natural quaternary isoquinoline alkaloid isolated from several medicinal plants that is traditionally used for various skin conditions was loaded in the vesicles. The developed nanovesicles were characterized in terms of diameter, polydispersity, ζ-potential, deformability, recovery, encapsulation efficiency, stability, and release kinetics. Nanovesicle permeation properties through artificial membranes and rabbit ear skin were investigated using skin-PAMPATM and Franz cells were also evaluated. Escinosomes, made of phosphatidylcholine and escin, were loaded with berberine chloride. These nanovesicles displayed the best characteristics for skin application, particularly optimal polydispersity (0.17) and deformability, high negative ζ-potential value, great encapsulation efficiency (about 67%), high stability, and the best release properties of berberine chloride (about 75% after 24 h). In conclusion, escinosomes seem to be new vesicular carriers, capable to maintain escin properties such as hyaluronidase inhibition activity, and able to load other active molecules such as berberine chloride, in order to enhance or expand the activity of the loaded drug.

Hypepontine, a new quaternary alkaloid with antimicrobial properties

New isoquinoline alkaloid hypepontine (1) together with a five known compounds, were identified in Hypecoum ponticum Velen, the partial synonym of Hypecoum procumbens L. The structure of the new substance was elucidated based on spectroscopic evidence. The tertiary and quaternary alkaloid mixtures as well as the isolated alkaloids were evaluated for their antibacterial and antifungal activity. The result revealed that the crude alkaloid mixture containing quaternary isoquinoline alkaloids showed potent antifungal and antibacterial activity.

Metabolic effects of the association Berberis aristata/Silybum marianum: a preliminary double-blind, placebo-controlled study in obese patients with type 2 diabetes

Berberine, a quaternary isoquinoline alkaloid present in Berberis aristata, is well known in terms of its cholesterol-lowering, hypoglycemic, and insulinsensitizer effects. Because of its low oral bioavailability, it has been recently formulated along with silymarin (Silybum marianum) to improve intestinal absorption. The aim of our study was to evaluate, versus placebo treatment, the possible effect of its association with silymarin on abdominal fat in overweight/obese patients affected by type 2 diabetes mellitus. Using bioelectrical impedance at enrolment and after 6 months of treatment, we have evaluated the following clinical parameters: waist circumference, trunk fat, and visceral fat. Our results seem to indicate a clinically significant effect for the association berberine+silymarin.

Neuraminidase inhibitory activities of quaternary isoquinoline alkaloids from Corydalis turtschaninovii rhizome

Clostridium perfringens is a Gram-positive spore-forming bacterium that causes food poisoning. The neuraminidase (NA) protein of C. perfringens plays a pivotal role in bacterial proliferation and is considered a novel antibacterial drug target. Based on screens for novel NA inhibitors, a 95% EtOH extract of Corydalis turtschaninovii rhizome showed NA inhibitory activity (68% at 30μg/ml), which resulted in the isolation of 10 isoquinoline alkaloids; namely, palmatine (1), berberine (2), coptisine (3), pseudodehydrocorydaline (4), jatrorrhizine (5), dehydrocorybulbine (6), pseudocoptisine (7), glaucine (8), corydaline (9) and tetrahydrocoptisine (10). Interestingly, seven quaternary isoquinoline alkaloids 1–7 (IC50=12.8±1.5 to 65.2±4.5μM) showed stronger NA inhibitory activity than the tertiary alkaloids 8–10. In addition, highly active compounds 1 and 2 showed reversible non-competitive behavior based on a kinetic study. Molecular docking simulations using the Autodock 4.2 software increased our understanding of receptor–ligand binding of these compounds. In addition, we demonstrated that compounds 1 and 2 suppressed bacterial growth.

ChemInform Abstract: Synthesis of 2‐Aryl‐3,4‐dihydroisoquinolin‐2‐ium Bromides and Their in vitro Acaricidal Activity Against Psoroptes cuniculi.

By employing sanguinarine, a natural active quaternary isoquinoline alkaloid, as a model molecule, a series of structurally simple quaternary 2-aryl-3,4-dihydroisoquinolin-2-ium compounds were designed and synthesized and evaluated for in vitro acaricidal activity against P. cuniculi. A new approach towards the title compounds was developed with isochroman as starting material. The results showed that 22 of 24 tested compounds displayed the activity in varying degrees at 0.4 mg/mL. Fourteen compounds were significantly more effective than ivermectin, a standard acaricide, and 6-methoxy dihydrosanguinarine, a derivative of sanguinarine (p<0.05). And their comprehensive relative activity was 1.4 to 16.5 times than that of ivermectin and 1.5 to 18.8 times than that of 6-methoxy dihydrosanguinarine. The structure-activity relationship indicated that the introduction of a substituent to N-benzene ring, especially halogen atom and trifluoromethyl group, led to great improvement of the activity. The position of fluorine atom, methyl group and hydroxyl group made very significant effects on the activity. It was concluded that 2-aryl-3,4-dihydroisoquinolin-2-iums are very promising candidates for the development of new isoquinoline acaricidal agents.