Abstract
Purpose
Rubus idaeus cultivation has boosted productivity due to its high nutritional value. In consequence, waste production increased. The discarded biomass, including leaves and aerial components, can be transformed into valuable functional ingredients for industrial applications, such as cosmetics. Studying their bioactivity potential is highly relevant.
Methods
According to the present idea, the research involved producing extracts from raspberry plant branches and leaves by employing four different techniques: aqueous decoction, aqueous infusion, hydroethanolic maceration, and ultrasound-assisted extraction (UAE). Subsequently, these compounds were screened for their bioactive potential, including antioxidant, antibacterial, anti-inflammatory, and cytotoxic properties.
Results
The ultrasound-assisted extraction produced extracts rich in phenolic compounds, whereas the infusion and maceration methods resulted in higher flavonol contents. Among the identified phenolic compounds, hydrolyzable tannins, particularly galloyl-bis-HHDP-glucose, were the most dominant ones. Regarding antioxidant potential, the decoction extract was the strongest, while the infusion showed the greatest potential for inhibiting lipid peroxidation. The UAE extract was found to be highly effective as an antibacterial agent. Both infusion and UAE extracts demonstrated the highest anti-inflammatory potential.
Conclusion
The combination of these results highlights the sample’s bioactive potential and the importance of exploiting bioresidues as unique, sustainable candidates for industrial applications.
Graphical Abstract
Statement of Novelty
This study examines the bioresidues of the Rubus idaeus species, a two-meter-high deciduous bush. Raspberries, known for their antioxidant properties, are widely exported, consumed, and used in various industrial sectors. A by-product of their cultivation, the leaves and other aerial parts, which are commonly used in infusions for having properties similar to berries, are emerging as an abundant and valuable raw material to be exploited as a source of functional ingredients, becoming an important focus of study. Their extracts hold important bioactivity, indicating the potential to be used in key industries such as cosmetics. In this context, this work addresses the full characterization of extracts obtained by different techniques, ultrasound-assisted, maceration, infusion, and decoction, envisaging identifying the ones with higher potential, focusing on antioxidant, antimicrobial, and anti-inflammatory applications.
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Introduction
This work comprised a study on a species from the Rubus genus belonging to the Rosaceae family: Rubus idaeus, a two-meter-high deciduous bush. Its white flowers produce a red and spherical berry fruit that grows on its branches, composed of many connected drupelets, which are individual sections of the fruit, each with its seed surrounding a central core, commonly called raspberry [1]. In general, berry species are widely known, and their fruits are appreciated for their antioxidant properties. In 2023, Serbia, Poland, and Chile were the leading exporters of raspberries [2,3,4,5]. The largest consumer of fresh and frozen raspberries was the United States [6].
Due to their short shelf-life, most traded raspberries are sold in frozen blocks and treated as a sensitive commodity that is subsequently used in beverages, teas, artificial sweeteners, and fruited wines. The production and harvested area of R. idaeus have increased, especially since 2003, reaching nearly 950 kilotons by 2022. Regarding its global distribution, Europe is responsible for 75.6% of the net production [7]. One solution for the generated bioresidues is the recovery and incorporation into new agri-food, cosmetic, or pharmaceutical products. Due to their high content of phenolic acids, flavonoids, and fibers, these by-products could be successfully recovered for different industrial purposes.
While raspberries have been extensively studied, their bioresidues remain underutilized. However, some findings suggest that leaves and other physiological parts obtained after harvesting could be a potential source of phenolic compounds with antioxidant and antimicrobial properties [8, 9]. These compounds have been reported as excellent antioxidants that could be used in cosmetic formulations.
Regular consumption of vegetables and fruits with high loads of polyphenols can help protect against the harmful effects of UV radiation. Moreover, they can provide health benefits like photoprotective properties, reducing oxidative stress, inflammation, and cancer risk. It is gaining attention from researchers in the cosmetic and pharmaceutical industries due to its cost-effectiveness [10]. Antioxidants can be a valuable tool to reduce oxidative damage in skin applications [11]. Since the start of the 21st century, there has been a growing trend towards using natural extracts, especially from plants. Many of these plants have adapted to the external environment by developing photo-adaptive mechanisms. These mechanisms include producing antioxidant and UV-absorbing compounds in response to intense radiation [10]. Cosmetic formulations with natural benefits are popular due to advances in plant constituent knowledge, human molecular biology, and cell physiology.
Natural extracts can provide the basis for a better cosmetic product benefiting the consumer [11]. A study on cosmetic formulations with natural products reported that the preparation of a topical skin cream formulation containing both placebo and raspberry extract gave rise to similar stability. This assay was preceded by a fruit extract selection between two different cultivars of Rubus idaeus, with the one presenting the better antioxidant capacity selected for the assay [12]. A recent report reported that the wild red raspberry variety R. idaeus has the highest concentration of anthocyanins and antioxidant compounds among other studied cultivars. Based on these findings, the authors decided to use the stem cells of R. idaeus to develop a new cosmetic active ingredient. Additionally, they extracted stem cells from the plant’s leaves, which had potential cosmetic applications [13].
One of the most significant characteristics to monitor as a guarantee of consumer safety is the microbiological quality of cosmetic products; therefore, preservatives are mandatory. However, bacteria have developed resistance to certain commonly used molecules, because their mechanisms of action are similar to those of antibiotics. On the other hand, their usage is restricted because it can harm human health at certain levels. Researchers face new problems in developing new products with anti-microbiological capabilities while remaining non-toxic to consumers, increasing the need for new biocidal compounds with excellent toxicological compatibility [14].
This study emphasizes the critical need to comprehensively analyze the bioactive compounds in raspberry bioresidues, evaluate various extraction techniques, and thoroughly investigate their antioxidant, antimicrobial, and anti-inflammatory properties for potential industrial applications. Therefore, the added value potential of the bioresidues resulting from the production of raspberry, namely from the pruning process, was evaluated. The obtained extracts were characterized by their content of phenolic compounds and studied according to the envisioned cosmetic future application through antioxidant, antimicrobial, and anti-inflammatory.
Materials and Methods
Plant Material
The aerial sections of Rubus idaeus were courteously donated by the private enterprise Hortitool Consulting Lda based in Baião, Portugal, a city located 577 m above sea level, in September 2019. After five days of air drying at ambient temperature (about 25 ºC), the raw material was ground to 20 mesh (0.8 mm) using a ZM200 Retsch-type grind. The dried material was then shielded from light and humidity until analysis.
Preparation of the R. Idaeus Extracts
Aqueous Extracts
Infusion
1 g of powdered sample was added to a boiling solution of 200 mL distilled water and kept for 5 min.
Decoction
After adding 1 g of powdered material to 200 mL of water, the mixture was boiled for 5 min.
The samples were gravity-filtered with a Whatman paper filter no. 4 for both aqueous extracts. After that, the aqueous extracts were frozen at -24 °C, lyophilized (Freeze Dryer Scanvac, Coolsafe, 4 × 10-4mbar, Lillerod, Denmark) at -100 °C, and stored in a dry environment.
Hydroethanolic Extracts
Maceration: 1 g of milled material was added to 30 mL of 80:20 ethanol-water solution and stirred at room temperature for an hour.
Ultrasound-assisted Extraction (UAE): This extraction was carried out in a sonicator (Qsonica, Q500, ultrasonic processor sonicator, 20 kHz, Newtown, USA) following the procedure described by Heleno et al. [15] with slight modifications to improve the extraction. In short, 1 g of powdered sample was mixed with 150 mL of an ethanol-water solution (80:20, v/v). To avoid scorching the samples, the extraction was carried out over 10 min, with 30-sec cycles and 10-sec pauses in between, at 375 W (75% of 500 W), using an ice bath.
The mixtures were gravity-filtered before evaporating the ethanol at 40 °C, 100 rpm, and 90 mbar under reduced pressure (Büchi R-114, rotary evaporator; Büchi B-480, water bath, and Büchi B-721, vacuum controlling system, Flawil, Switzerland). The aqueous residue was then lyophilized, stored in a dry chamber, and then frozen at -24 °C.
The extracts were subjected to UV decontamination before each bioactivity evaluation.
Chemical Characterization in Terms of Phenolic Compounds
The phenolic compounds in each extract were identified and quantified using the procedure described by Bessada et al. [16]. Each 10 mg of weighed sample was dissolved in 1 mL of ethanol-water solution (20:80 v/v), then filtered through a 0.22 μm disposable filter. The phenolic profile was determined using a Dionex Ultimate 3000, a high-performance liquid chromatographic system with a diode array detector and an electrospray ionization mass spectrometry detector (HPLC-DAD-ESI/MS) (Dionex Ultimate 3000 UPLC and Linear Ion Trap LQT XL, Thermo Scientific, San Jose, CA, USA).
To quantify the identified molecules, calibration curves were developed for each chemical using authentic standards (Extrasynthése S.A., Genay, France). The phenolic compounds contained in the extracts were identified using the referred standards and data from the literature. The Xcalibur® data system was used to collect and process the data (Thermo Scientific, San Jose, CA, USA). The results were provided in mg per g of extract.
Bioactive Properties
Antibacterial Activity
Different bacterial strains isolated from hospitalized patients (Hospital Center of Trás-os-Montes e Alto Douro, Vila Real, Portugal) were tested to determine the antibacterial capacity of the developed extracts, namely five Gram-negative bacteria: Escherichia coli (isolated from urine), Proteus mirabilis (isolated from wound exudate), Klebsiella pneumoniae (isolated from urine), Pseudomonas aeruginosa (isolated from expectoration) and Morganella morganii (isolated from urine); and three Gram-positive bacteria: Enterococcus faecalis (isolated from urine), Listeria monocytogenes (isolated from cerebrospinal fluid), and methicillin-resistant Staphylococcus aureus (MRSA) (isolated from expectoration). As indicated in the work of Pires et al. [17], the experiment was carried out using the microdilution technique with the addition of de p-iodonitrotetrazolium chloride (INT) (Panreac Applichem-Barcelona, Spain) as a marker. Ampicillin (0.15 to 20 mg/mL), imipenem, and vancomycin (0.0078 to 1 mg/mL) were positive controls. Bacterial viability control was also created using the medium applied with each bacterial strain. The extracts were evaluated at various concentrations, and the minimum inhibitory/bactericidal concentrations (MIC/MBC) were calculated and represented as mg per mL.
Antioxidant Activity
The study used two tests, Oxidative Haemolysis Inhibition (OxHLIA) and Thiobarbituric Acid Reactive Substances (TBARS), to measure the antioxidant activity. The OxHLIA test was conducted based on Lockowandt et al. [18], which monitored the extracts’ ability to protect erythrocyte membranes against free radical-induced oxidation. The extracts were dissolved in phosphate-buffered saline (PBS) to create a stock solution of 1.0 mg/mL, which was then diluted to make various working concentrations. Trolox (7.81–250 g/mL) was utilized as a positive control. The findings were presented as IC50 values (µg/mL) for Δt of 60 and 120 min, indicating the extract concentration needed to preserve 50% of the erythrocyte population unharmed for 60 and 120 min, respectively.
The TBARS experiment was performed according to Gómez-Mejía et al. [19], in which the ability of the extracts to prevent lipidic peroxidation is measured by the decrease of TBARS formation via the creation of malondialdehyde (MDA)-TBA, which can be measured at 532 nm (Specord 200 spectrophotometer, Analytik Jena, Jena, Germany). The EC50 values were calculated using Trolox as a positive control and expressed as the concentration (mg/mL) providing 50% antioxidant activity.
Cytotoxicity
The extracts were tested against MCF-7, NCI-H460, AGS, and CaCo2 cell lines representing breast adenocarcinoma, non-small-cell lung cancer, gastric adenocarcinoma, and colorectal adenocarcinoma, respectively. The non-tumour cell line consisted of porcine liver cells (PLP2) and African green monkey kidney cells (VERO), using the sulphorodamine B technique to detect the potential toxicity of the produced extracts in non-tumour cell lines [20]. The extracts were evaluated in a 400 to 1.56 mg/mL concentration range using a positive control, ellipticine. The GI50 values, representing the concentration inhibiting 50% of cell growth, were measured in µg/mL.
Anti-Inflammatory Activity
Mice macrophage cell lines (RAW264.7) were adopted in this study, according to the technique described by Taofiq et al. [21]. Different concentrations of the extracts were evaluated, ranging from 400 to 1.56 µg/mL. This effect was established on the extract’s ability to suppress NO generation, resulting in an active concentration with anti-inflammatory properties. NO generation was measured in a microplate reader (Bio-Tek Instruments, ELX800) using dexamethasone as the positive control and absorbance at 540 nm for a calibration curve.
Statistical Analysis
Experiments were conducted in triplicate, and findings were given as average ± standard deviation. The data was analysed using an analysis of variance (ANOVA), with a Tukey’s test for homoscedastic samples and a Tamhane T2 for non-homoscedastic samples. When comparing two independent samples, the variance was analysed using a t-test. All analyses were performed at a threshold of significance of 0.05.
Results and Discussion
Phenolic Compounds
Table 1 shows the chromatographic characteristics, tentative identification, and individual quantification of phenolic compounds in R. idaeus leaf extracts obtained by HPLC-DAD/ESI-MS. Sixteen phenolic compounds were tentatively identified: five phenolic acids (ellagic and chlorogenic acid derivatives), three flavonoids (one flavonol and two flavan-3-ols), and eight hydrolysable tannins.
Peak 1 ([M − H]– at m/z 633) and peaks 8–10 ([M − H]– at m/z 935) were assigned as hexahydroxydiphenoyl group, being identified as galloyl-HHDP-glucose and galloyl-bis-HHDP-glucose, respectively. The fragment at m/z 301 represented evidence of the presence of an (HHDP) group [ellagic − H]− in the molecule [22]. Raspberry leaf extracts have revealed the presence of compounds that showed a UV spectrum coherent with galloyl and HHDP derivatives [23], confirming these identifications. Peaks 5 and 6 ([M − H]− at m/z 783) were assigned to pedunculagin isomers according to their pseudomolecular ion and fragmentation pattern as described by [24, 25]. Similarly, peak 7 ([M − H]− at m/z 1251) was identified as punicalagin gallate [26].
Peak 2 ([M − H]– at m/z 355) was tentatively identified as dihydrocaffeoylquinic based on the parent ion, leading to the MS2 base peak of m/z 191, corresponding to dihydrocaffeic acid, mainly because of the neutral loss of 164 u.
Peaks 11–14 were tentatively identified as ellagic acids derivatives. Thus, peaks 11 and 14 ([M − H]− at m/z 433) were assigned as ellagic acid pentoside, producing a base fragment at m/z 301, corresponding to a deprotonated ellagic acid, revealing the loss of a pentose moiety (− 132 u). Similarly, peak 12 ([M − H]− at m/z 477) was tentatively identified as a methyl ellagic acid hexoside. Peak 13 was positively identified as ellagic acid according to its retention time, mass spectra, and UV–Vis characteristics by comparison with standards found in the market. According to the literature, Rubus leaves are rich in ellagic acid derivatives [27, 28], where ellagic acid may occur in its free form but also be released through the hydrolysis of ellagitannins [23, 29, 30].
Flavan-3-ols were also detected in raspberry leaves, revealing peaks 3 ([M − H]− at m/z 577) and 4 ([M − H]− at m/z 865) a λmax spectra around 276–281 nm, characteristic of this group of compounds, these compounds were tentatively assigned to a procyanidin dimer and procyanidin trimer, respectively. The only flavone (peak 15) detected was positively identified compared to a commercial standard.
Hydrolysable tannins, including peaks 1, 5–10, and 16, were the primary phenolic compounds in R. idaeus leaf extracts. Considering the different extraction methods, ultrasound-assisted extraction was more effective in extraction in terms of total phenolic compounds (109 ± 3 mg/g of extract), while for the flavonols and flavan-3-ols class, the most efficient extraction method was infusion and maceration.
Altogether, the extracted phenolic compounds are abundant, giving those extracts the characteristics sought for cosmetic use. Previous studies show that extracts high in polyphenols are useful for treating and preventing oxidative stress-induced premature skin aging. Polyphenols’ advantageous characteristics, which are especially pertinent for topical administration, include antioxidant activity, protection against UV damage, inhibition of skin proteinases, antimicrobial activity, and anti-carcinogen action [31].
Ellagic acid may lead to improvement of hyperpigmentation and dark spots, melasma, increased UV damage protection, and seems to have antiwrinkle activity, according to Sharifi-Rad et al. [32]. Chlorogenic acid’s skin-related benefits are antioxidant and anti-aging, photoprotective and antitumor, anti-inflammatory, and antibacterial [33]. Procyanidin possesses antioxidant, antitumor, anti-inflammatory, immunosuppressive, antiallergy properties and protective properties against chronic diseases and metabolic disorders [34]. The identified flavone, luteolin-7-O-glucuronide, may be an ideal candidate to alleviate severe inflammatory responses and oxidative stress, according to Cho et al. [35].
The major phenolic compound present, galloyl-bis-HHDP-glucose, is described in the literature as exerting anti-inflammatory effects [36, 37]. Pedunculagin isomers, other hydrolyzable tannins, are described as antioxidants and anticancer [38].
Bioactive Potential
Antibacterial Activity
The microdilution method was used to study the antibacterial properties against pathogenic bacteria. All extracts inhibited most of the tested bacterial strains, with UAE extracts being the most effective. UAE samples inhibited the Gram-negative bacteria E. coli, K. pneumoniae, M. morganii, and P. mirabilis with a 5 mg/mL MIC. In a report by Khalifa et al. [39], when studying raspberry aqueous extracts to inhibit E. coli and P. aeruginosa, concentrations of 25 mg/mL and 50 mg/mL were used. Also, in that work, a MIC of 25 mg/mL against L. monocytogenes was found; in the present work, 5 mg/mL was determined.
Regarding the Gram-positive bacteria, for raspberry UAE extract a MIC of 2.5 mg/mL against E. faecalis and the methicillin-resistant S. aureus was achieved. In contrast, previous works have achieved a MIC of 50 mg/mL for this last strain with aqueous raspberry extracts [39].
In another report, Krauze-Baranowska et al. [40] studied the antimicrobial activity of raspberry shoot aqueous extracts, reporting a MIC of 60 mg/mL against K. pneumoniae and 120 mg/mL against E. faecalis, whereas in this work, a MIC of 5 mg/mL and 2.5 mg/mL respectively, were determined. That report presented better results using the MRSA, where a MIC of less than 1 mg/mL was achieved compared with the present work’s best result of 2.5 mg/mL using the UAE extract. In another study, Bauza-Kaszewska et al., [41] found that all three R. idaeus preparations tested (seedless, seeds, and pomace) had no or low antibacterial activity against the tested microorganisms, one of which being L. monocytogenes, which was also studied in the current study in which the infusion extract presented a MIC of 5 mg/mL.
Regarding Minimum Bactericidal Concentration (MBC) results, none of the studied extracts presented bactericide effects. Khalifa et al. [39] determined bactericide results against the Gram-negative strain P. aeruginosa and the Gram-positive L. monocytogenes, finding a 100 mg/mL result for both.
Krauze-Baranowska et al. [40] obtained a MBC of 120 and 60 mg/mL alongside E. faecalis and K. pneumoniae, respectively. Again, the present work obtained a better result against MRSA, with an MBC of 1 mg/mL. Thus, the tested extracts could be used as bioactive compounds capable of inhibiting the bacterial growth of some pathogenic strains.
Antimicrobial activity is an important bioactivity in the development of a cosmetic, as it contributes to increasing the final product’s shelf life. The antimicrobial activity of extracts from raspberry residues can be explained by the presence of dihydrocaffeoylquinic acid [33].
Antioxidant Activity
The study evaluated the antioxidant activity of raspberry extracts from its aerial parts using two methods - OxHLIA and TBARS (Table 3). Among the extracts, the one obtained through decoction showed the highest antioxidant activity after 60 min, followed by macerations. However, no significant differences were found between the antioxidant activities of the extracts obtained through infusion and UAE. At 120 min, the only statistical difference found was between infusion and UAE. At 60 min, none of the samples showed better activity than the positive control, Trolox. However, decoction had a similar response, while at 120 min, both the decocted and macerated samples showed better activity than the pure compound (Trolox). Comparing the two analysis times, for all extraction types, the best antioxidant activity was found after 60 min, with a statistically significant decrease at 120 min. Considering the TBARS assay, the best extract was the one of infusion, showing a statistically lower EC50 than the maceration. In contrast, the decoction and UAE did not show significant differences. The differences in the antioxidant activity between the two assays are mostly related to the antioxidant mechanisms of each assay.
As reported in a previous work involving the study of leaf extracts from seven different raspberry cultivars concerning their antioxidant activity, they showed values of 88.1 mmol of Trolox equivalents for the most active sample [27]. Vara et al. [42] studied red raspberry hydroethanolic extracts, which presented an IC50 of 298 µg/mL for OxHLIA and an EC50 of 122 µg/mL for TBARS assay. Thus, R. idaeus aerial parts presented better antioxidant activity than its fruits.
UV light and pollutants may also produce oxidative stress, depleting the natural antioxidant reserve. This can lead to loss of cellular integrity, increased matrix metalloproteinases, wrinkle formation, metastases, and peroxidation of fatty acids. Natural polyphenols have shielding effects against radical oxygen species, highlighting their potential for anti-aging applications. Antioxidant activity manifested by raspberry waste extracts can be explained by the presence of dihydrocaffeoylquinic acid, luteolin-7-O-glucuronide, pedunculagin isomers, and primarily due to procyanidin.
Cytotoxicity
The UAE and infusion extracts showed the lowest IC50 values in the anti-inflammatory assay, indicating stronger activity. Still, the ones obtained by infusion did not show statistically significant differences towards the maceration sample. Finally, the decoction was the least effective extraction type regarding anti-inflammatory activity. The UAE was also the extract with higher antitumor activity against all tested cell lines, showing statistically significant lower IC50 values than the extracts obtained by the other techniques. This indicates that UAE preserves polyphenols with higher biological properties towards cell lines. Still, none of the samples showed an activity close to the positive controls. In terms of cytotoxicity to normal cell lines, none of the extraction techniques showed extracts with toxicity, representing more than 400 cells per plate.
Proof of the cytotoxic safety of extracts from raspberry bioresidues allows taking advantage of their excellent antitumor and anti-inflammatory properties. The antitumor behavior can be mainly attributed to dihydrocaffeoylquinic acid and procyanidin isomers and, in a more residual way, to pedunculagin. Inflammation is a tissue’s defense mechanism against pathogen invasions, cell injury, and irritation, and it acts as a means of removing injured and necrotic cells. It can be acute or chronic, and chronic inflammation is thought to be a major factor in the emergence of chronic illnesses. The studied extracts have been shown to have relevant anti-inflammatory properties. They may have been evidenced by the major presence of the compound galloyl-bis-HHDP-glucose, as well as dihydro caffeoylquinic acid, procyanidin isomers, and luteolin-7-O-glucuromide, also present in the extracts.
Conclusions
The exponential evolution of waste biomass derived from berry crops, including raspberry, is a new focus of study. In fact, producers are increasingly interested in its valorisation in high-added-value products, under the European Commission’s recommendations to achieve the zero-waste goal. According to the data obtained from the various types of extractions, all the employed methods enabled the obtention of the target molecules, namely phenolic compounds, which exhibited bioactive potential. It should be noted that the tested extraction techniques may be used to achieve significant quantities of phenolics; for example, in the UAE, achieving the greatest yields for some of the key compounds was possible. Maceration was the most effective technique for extracting phenolic acids and flavonols. In terms of bioactivity, all of the extracts were active, with the UAE extract being the most active. The antioxidant capabilities of the extracts were also shown to be favourably linked with the level of hydrolysable tannins. These findings highlight the sample’s bioactive potential and the necessity of exploiting bioresidues as distinct options for industrial applications by harnessing their biological properties. In this sense, the leaves and other aerial components are good examples of waste biomass that can be exploited for several applications, namely cosmetic formulations.
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Acknowledgements
The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) for financial support through national funds FCT/MCTES (PIDDAC) to CIMO (UIDB/00690/2020 and UIDP/00690/2020) and SusTEC (LA/P/0007/2020); the contract of L. Barros and S. Heleno through the institutional scientific employment program-contract, the contract of M. Carocho (CEEC-IND/00831/2018). To FCT for the PhD studentship granted to M. Añibarro-Ortega (2020.06297. BD). To the “La Caixa” Foundation and to FCT for the financial support through Project “Aquae Vitae — Thermal water as a source of life and health”, Promove Mobilizer programme. The authors would also like to thank Hortitool Consulting Lda., for the samples that were given to proceed with this project.
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Plasencia, P., Finimundy, T.C., Carocho, M. et al. Extraction of Bioactive Compounds from Rubus Idaeus Bioresidues: A Full Screening on Phenolic Composition and Bioactive Potential. Waste Biomass Valor (2024). https://doi.org/10.1007/s12649-024-02696-w
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DOI: https://doi.org/10.1007/s12649-024-02696-w