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Berberis darwinii, known for its bioactive alkaloids like berberine and palmatine, has gained attention for its medicinal properties. However, comprehensive studies on the specific bioactive molecules of Michay are lacking, as previous research has primarily focused on wild plants. Therefore, this study proposes to evaluate the alkaloid content in various tissues of B. darwinii collected from different locations, aiming to identify high-yielding accessions suitable for consistent bioactive alkaloid production. This research focuses on plants from a cultivated Michay orchard established five years ago. Leaves, stems, roots, and fruits from 96 accessions of Michay were collected to obtain an alkaloidal extract used for the characterization and comprehensive analysis of bioactive alkaloids through high-performance liquid chromatography. Based on these results, a search for the main outliers was conducted to identify the accessions with the highest alkaloid production. The results showed that roots had the highest concentrations of both berberine and palmatine, followed by stems, while leaves and seeds had lower levels, and the pulp from fruits had no detectable alkaloids. Notably, alkaloid concentrations reached up to 30,806 µg/g in roots, with accession C2P18 standing out for its combined total of 20,827.74 µg/g of berberine and 9978.27 µg/g of palmatine. Accession C3P26 showed the highest berberine concentration at 26,482.20 µg/g. These values underscore the wide variation in alkaloid accumulation and highlight the potential for selecting elite accessions with exceptionally high yields. These findings highlight the importance of plant selection for optimal alkaloid extraction. Choosing high-yielding accessions and standardizing cultivation practices will ensure a stable supply of berberine and palmatine for pharmaceutical, nutraceutical, and food industry applications.

The magnetization strategy of isoquinoline alkaloids has been successfully used in the extraction and isolation, but the effect of the magnetization on biological activities of those alkaloids still deserves further investigation. Therefore, the antibacterial, lipid-lowering and antioxidant activities of five isoquinoline alkaloids (berberine, tetrahydroberberine, palmatine, tetrahydropalmatine and tetrahydropapavine) before and after magnetization were compared in this study, and the results showed that the relevant activities were enhanced after magnetization. Additionally, among the five magnetic derivatives studied, berberine magnetic derivative ([Ber·H] + [FeCl 4 ] − ) had the best antibacterial effect on S. aureus and E. coli with MIC of 200 and 800 µM, respectively; palmatine magnetic derivative ([Pal·H] + [FeCl 4 ] − ) showed the strongest lipid-lowering activity with IC50 of 429 mM, and the inhibitory effect and type on lipase was reversible and mixed inhibition of competition and non-competition type; tetrahydroberberine magnetic derivative ([THBer·H] + [FeCl 4 ] − ) had the strongest antioxidant activity. This study provides new ideas and references for the further application of magnetization strategy.

In this paper, the selective interactions of synthetic derivatives of two natural compounds, berberine and palmatine, with DNA G-quadruplex structures were reported. In particular, the previous works on this subject concerning berberine were further presented and discussed, whereas the results concerning palmatine are presented here for the first time. In detail, these palmatine derivatives were developed by inserting seven different small peptide basic chains, giving several new compounds that have never been reported before. The preliminary studies of the interactions of these compounds with various G-quadruplex-forming sequences were carried out by means of various structural and biochemical techniques, which showed that the presence of suitable side chains is very useful for improving the interaction of the ligands with G-quadruplex structures. Thus, these new palmatine derivatives might act as potential anticancer drugs.

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. Graphic abstract

The effective treatment of Alzheimer’s disease (AD) is challenging because of its complex and controversial pathological mechanisms. Moreover, multiple barriers, such as the blood–brain barrier (BBB), reduce drug delivery efficiency. Microglia-related neuroinflammation has recently attracted increasing attention as a possible cause of AD and has become a novel therapeutic target. Therefore, overcoming the BBB and targeted delivery of anti-inflammatory agents to microglia seem to be effective practical strategies for treating AD. A large proportion of natural active extracts possess exceptional immunomodulating capabilities. In this study, the cooperative delivery of berberine (Ber) and palmatine (Pal) by transferrin-decorated extracellular vesicles (Tf-hEVs-Ber/Pal), which can cross the BBB and precisely target microglia, was performed. This nanosystem effectively cleared amyloid β-protein (Aβ) aggregates, significantly regulated the neuroinflammatory environment both in vitro and in vivo and markedly altered the behavior and improved the cognitive and learning abilities of AD model mice. The efficacy of a microglia-targeting combined therapeutic approach for AD was demonstrated, which broadens the potential application of Chinese herbal ingredients. Graphical abstract

Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR) activation and cytochrome P450 (CYP) 1 in the estrogen receptor (ER)α(+) MCF-7 breast cancer cells. Among protoberberines at non-cytotoxic concentrations (≤10 μM), berberine had the most potent and statistically significant effects on AhR activation and CYP1A1/1A2/1B1 mRNA induction. The 24-h exposure to 10 μM berberine did not change CYP1A1 mRNA stability, protein level and function. Berberine significantly increased micro RNA (miR)-21-3p by 36% and the transfection of an inhibitor of miR-21-3p restored the induction of CYP1A1 protein with a 50% increase. These findings demonstrate that the ring opening of the methylenedioxyl moiety in berberine decreased AhR activation in MCF-7 cells. While CYP1A1 mRNA was elevated, berberine-induced miR-21-3p suppressed the increase of functional CYP1A1 protein expression.

By introducing long carbon-chain alkyl groups at the C-13 position of berberine and palmatine, 13-n-hexyl/13-n-octyl berberine and palmatine chloride analogues 4a–d were synthesized and examined by MTT assays for cytotoxic activity in seven human cancer cell lines (7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, KIII, Lewis), yielding IC50 values of 0.02 ± 0.01–13.58 ± 2.84 μM. 13-n-Octyl palmatine (compound 4d) gave the most potent inhibitor activity, with an IC50 of 0.02 ± 0.01 μM for SMMC7721. In all cases, the 13-n-alkyl berberine and palmatine analogues 4a–d were more cytotoxic than berberine and palmatine. In addition, compounds 4a–d also exhibited more potent cytotoxicity than berberine and palmatine in mice with S180 sarcoma xenografted in vivo. The primary screening results indicated that the 13-n-hexyl/13-n-octyl berberine and palmatine analogues might be valuable source for new potent anticancer drug candidates.

Background Protoberberine alkaloids are bioactive molecules abundant in plant preparations for traditional medicines. Yeast engineered to express biosynthetic pathways for fermentative production of these compounds will further enable investigation of the medicinal properties of these molecules and development of alkaloid-based drugs with improved efficacy and safety. Here, we describe the optimization of a biosynthetic pathway in Saccharomyces cerevisiae for conversion of rac -norlaudanosoline to the protoberberine alkaloid ( S )-canadine. Results This yeast strain is engineered to express seven heterologous enzymes, resulting in protoberberine alkaloid production from a simple benzylisoquinoline alkaloid precursor. The seven enzymes include three membrane-bound enzymes: the flavin-dependent oxidase berberine bridge enzyme, the cytochrome P450 canadine synthase, and a cytochrome P450 reductase. A number of strategies were implemented to improve flux through the pathway, including enzyme variant screening, genetic copy number variation, and culture optimization, that led to an over 70-fold increase in canadine titer up to 1.8 mg/L. Increased canadine titers enable extension of the pathway to produce berberine, a major constituent of several traditional medicines, for the first time in a microbial host. We also demonstrate that this strain is viable at pilot scale. Conclusions By applying metabolic engineering and synthetic biology strategies for increased conversion of simple benzylisoquinoline alkaloids to complex protoberberine alkaloids, this work will facilitate chemoenzymatic synthesis or de novo biosynthesis of these and other high-value compounds using a microbial cell factory.

Huang-Lian-Jie-Du-Tang (HLJDT), a traditional formula with four TCM herbs, has been used for hundred years for different diseases. The current study aimed to assess the inhibitory activity of HLJDT against H1N1 neuraminidase (NA-1), and identify potent NA-1 inhibitors from its plasma profile. The in vitro NA-1 study has shown that the water extract of HLJDT potently inhibited NA-1 (IC 50  = 112.6 μg/ml; Ki = 55.6 μg/ml) in a competitive mode. The IC 50 values of the water extracts of its four herbs were as follows: Coptidis Rhizoma, 96.1 μg/ml; Phellodendri Chinensis Cortex, 108.6 μg/ml; Scutellariae Radix, 303.5 μg/ml; Gardeniae Fructus, 285.0 μg/ml. Thirteen compounds found in the plasma profile of HLJDT were also identified as potent NA-1 inhibitors, which included jatrorrhizine, palmatine, epiberberine, geniposide, oroxylin A, berberine, coptisine, baicalein, wogonoside, phellodendrine, wogonin, oroxylin A-7-O-glucuronide and baicalin (sorted in ascending order by their IC 50 values). Their inhibitory activities were consistent with molecular docking analysis when considering crystallographic water molecules in the ligand-binding pocket of NA-1. Our current findings suggested that HLJDT can be used as a complementary medicine for H1N1 infection and its potent active compounds can be developed as NA-1 inhibitors.

Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood–brain barrier was determined via quantitative structure–activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.