Comprehensive Analysis of Berberis aristata DC. Bark Extracts: In Vitro and In Silico Evaluation of Bioaccessibility and Safety
Abstract
:1. Introduction
- (1)
- the phytochemical characterization of sixteen different commercial raw BER-containing ingredients, used in food supplement formulation, through the development of an efficient HPLC-DAD method to quantify BER and PROTBERs;
- (2)
- In Vitro evaluation of digestive stability and bioaccessibility, and In Silico investigation of pharmacokinetic properties of BER and PROTBERs;
- (3)
- prediction of potential BER-related targets by bioinformatic analysis;
- (4)
- assessment of cytotoxicity in In Vitro human intestinal (Caco-2), hepatic (HepG2), gastric (AGS), and kidney (HEK293) cell lines, and of BER’s impact on hepatic cell viability in the presence of CYP450 substrates;
- (5)
- evaluation of BER’s effects on cell migration ability of colorectal carcinoma cells (Caco-2);
- (6)
- investigation of potential oxidative stress of BER in non-tumoral kidney cells (HEK293) by the dosage of ROS;
- (7)
- evaluation of the transcriptional effects of BER on the main target genes involved in the regulation of cell cycle, cell growth, and neoplastic transformation, as well as on oncogenes.
2. Materials and Methods
2.1. Plant Material
2.2. Phytochemical Analysis
2.3. In Vitro Bioaccessibility Assessment
2.4. In Silico Pharmacokinetic Analysis and Target Prediction
2.5. In Vitro Cell Culture and Treatment
2.6. Cytotoxicity Assay
2.7. Cytotoxicity Assay in Presence of CYP450 Substrates
2.8. Dosage of Intracellular Reactive Oxygen Species (ROS) Level
2.9. Migration Assay
2.10. Total RNA Extraction, Reverse Transcription, and Real-Time PCR
2.11. Statistical Analysis
3. Results
3.1. Chemical Analyses of Extracts Containing Berberine and Protoberberinoids
3.2. In Vitro Bioaccessibility Assessment of Berberine and Protoberberinoids
3.3. In Silico Pharmacokinetic Analysis and Target Prediction of Berberine and Protoberberine Derivatives
3.4. In Vitro Cytotoxicity Evaluation of Berberis aristata Bark Extracts
3.5. In Vitro Cytotoxicity Evaluation of Berberis aristata Bark Extracts in Presence of CYP450 Substrates
3.6. Effect of Berberis aristata Bark Extracts on Cell Migration
3.7. In Vitro Evaluation of ROS Production in Normal Kidney Cells Treated with Berberis aristata Bark Extracts
3.8. Transcriptional Effects of Berberis aristata Bark Extracts on Target Genes Involved in Cell Cycle Control and Neoplastic Transformation
4. Discussion
5. Conclusions
- (i)
- The study addresses the bioaccessibility and safety of berberine and protoberberinoids through a highly transferrable conceptual framework. It focuses on the most widely recognized and utilized extracts available in the food supplement market, which have been chemically characterized;
- (ii)
- Integrated In Silico and In Vitro approaches provide valuable insights. The study concurrently evaluates the bioaccessibility of the examined samples, the impact of Berberis aristata extracts on hepatic toxicity in the presence of CYP450 substrates, the effects of cell toxicity and cell migration on tumor cells, and the potential pro-oxidant and pro-tumoral effects in non-tumoral human cells;
- (iii)
- The protocol employed considers different exposure times and treatment concentrations, enhancing the robustness of the In Vitro models used.
- (i)
- In future research, we intend to expand the pharmacokinetic evaluation of the major alkaloids contained in B. aristata extracts, including dynamic cell absorption models;
- (ii)
- While the current focus was on gene expression and transcriptional response to investigate early cellular response, we plan to explore the impact of berberine and protoberberinoids on human cell lines by examining upstream and downstream cell signaling pathways and protein levels related to antiproliferative activity;
- (iii)
- Finally, we are fully aware that our findings are derived solely from In Vitro tests, and further confirmation through additional studies is necessary.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | NCBI GenBank | Sequence |
---|---|---|
Rplp13a | NM_012423.4 | fw: GTGCGTCTGAAGCCTACAAG rv: CGTTCTTCTCGGCCTGTTTC |
Rps18 | NM_022551.3 | fw: TCTAGTGATCCCTGAAAAGT rv: AACACCACATGAGCATATC |
Tp53 | NM_000546.6 | fw: AGGGATGTTTGGGAGATGTAAG rv: CCTGGTTAGTACGGTGAAGTG |
c-Myc | NM_001354870.1 | fw: AAGCTGAGGCACACAAAGA rv: GCTTGGACAGGTTAGGAGTAAA |
n-Myc | NM_005378.6 | fw: TCCAGCAGATGCCACATAAG rv: ACCTCTCATTACCCAGGATGTA |
Met | NM_001127500.3 | fw: CCTGGGCACCGAAAGATAAA rv: CTCCTCTGCACCAAGGTAAAC |
Mdm2 | NM_002392.6 | fw: AGGCTGATCTTGAACTCCTAAAC rv: CAGGTGCCTCACATCTGTAATC |
Cdkn1a | NM_000389.5 | fw: CGGAACAAGGAGTCAGACATT rv: AGTGCCAGGAAAGACAACTAC |
Snai1 | NM_005985.4 | fw: CAGATGAGGACAGTGGGAAAG rv: GAGACTGAAGTAGAGGAGAAGGA |
Snai2 | NM_003068.5 | fw: AACTACAGCGAACTGGACAC rv: GAGGATCTCTGGTTGTGGTATG |
Hras | NM_005343.4 | fw: AAGCAAGGAAGGAAGGAAGG rv: GTGGCATTTGGGATGTTCAAG |
Cdk4 | NM_000075.4 | fw: GCTCTGCAGCACTCTTATCTAC rv: CTCAGTGTCCAGAAGGGAAATG |
Bax | NM_004324 | fw: CTCCCCATCTTCAGATCATCAG rv: GGCAGAAGGCACTAATCAAGTC |
Bcl2 | NM_000657 | fw: GACTGAGTACCTGAACCGGC rv: CTCAGCCCAGACTCACATCA |
Parameter | Value |
---|---|
R2 | 0.99 |
Equation | y = 4317.80 − 98.57 |
Linearity range | 0.04–7.5 μg in column |
Recovery of spiked standard | >90% and <105% |
Limit of quantification | 0.03 μg in column |
Intra- and inter-day variation | <3% |
Sample | Berberine % w/w db | Sample | Berberine % w/w db |
---|---|---|---|
A85 | 86.26 | A97 | 97.41 |
B85 | 86.74 | B97 | 91.94 |
C85 | 91.93 | C97 | 96.50 |
D85 | 88.87 | D97 | 97.16 |
E85 | 89.63 | E97 | 97.49 |
F85 | 90.66 | F97 | 97.21 |
G85 | 80.07 | G97 | 97.29 |
J85 | 87.88 | J97 | 97.80 |
mean ± SD | 87.76 ± 3.64 | mean ± SD | 96.60 ± 1.91 |
Samples | Jatrorrhizine % w/w db | Berberrubine + Palmatine % w/w db |
---|---|---|
A85 | 2.39 | 0.25 |
B85 | 1.88 | 0.24 |
C85 | 2.10 | 0.23 |
D85 | 3.07 | 0.26 |
E85 | 2.54 | 0.28 |
F85 | 2.85 | 0.24 |
G85 | 2.59 | 0.20 |
J85 | 3.12 | 0.25 |
mean ± SD | 2.57 ± 0.44 | 0.24 ± 0.02 |
A97 | 2.25 | 0.24 |
B97 | 1.49 | 0.08 |
C97 | 2.98 | 0.11 |
D97 | 2.57 | 0.23 |
E97 | 2.04 | 0.13 |
F97 | 2.04 | 0.14 |
G97 | 2.05 | 0.28 |
J97 | 1.71 | 0.13 |
mean ± SD | 2.14 ± 0.46 | 0.17 ± 0.07 |
Samples | Berberine % w/w db | Jatrorrhizine % w/w db | Berberrubine + Palmatine % w/w db |
---|---|---|---|
B. aristata 85% (B85) | 87.57 ± 1.85 | 2.83 ± 0.48 | 0.26 ± 0.01 |
B. aristata 97% (B97) | 97.35 ± 0.08 | 2.15 ± 0.14 | 0.26 ± 0.02 |
Bioaccessibility Rate % | ||
---|---|---|
Samples | Berberine | Jatrorrhizine |
B. aristata 97% | >95 | 83.57 ± 3.33 |
B. aristata 85% | >95 | 87.81 ± 3.69 |
IC50 (µg/mL) | |||||
---|---|---|---|---|---|
Sample | Treatment (h) | AGS | Caco-2 | HepG2 | HEK293 |
B97% | 4 | >200 | 166.93 ± 8.44 | >200 | 142.65 ± 12.01 |
B85% | 4 | >200 | 169.14 ± 9.25 | >200 | 181.93 ± 24.50 |
B97% | 24 | >200 | 105.59 ± 11.21 | 198.85 ± 8.50 | 127.16 ± 25.18 |
B85% | 24 | >200 | 107.34 ± 9.68 | 186.41 ± 8.42 | 143.43 ± 29.80 |
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Rigillo, G.; Cappellucci, G.; Baini, G.; Vaccaro, F.; Miraldi, E.; Pani, L.; Tascedda, F.; Bruni, R.; Biagi, M. Comprehensive Analysis of Berberis aristata DC. Bark Extracts: In Vitro and In Silico Evaluation of Bioaccessibility and Safety. Nutrients 2024, 16, 2953. https://doi.org/10.3390/nu16172953
Rigillo G, Cappellucci G, Baini G, Vaccaro F, Miraldi E, Pani L, Tascedda F, Bruni R, Biagi M. Comprehensive Analysis of Berberis aristata DC. Bark Extracts: In Vitro and In Silico Evaluation of Bioaccessibility and Safety. Nutrients. 2024; 16(17):2953. https://doi.org/10.3390/nu16172953
Chicago/Turabian StyleRigillo, Giovanna, Giorgio Cappellucci, Giulia Baini, Federica Vaccaro, Elisabetta Miraldi, Luca Pani, Fabio Tascedda, Renato Bruni, and Marco Biagi. 2024. "Comprehensive Analysis of Berberis aristata DC. Bark Extracts: In Vitro and In Silico Evaluation of Bioaccessibility and Safety" Nutrients 16, no. 17: 2953. https://doi.org/10.3390/nu16172953