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We examined the inhibitory activity of angiotensin I converting enzyme (ACE) in protein hydrolysates from dulse, Palmaria palmata. The proteins extracted from dulse were mainly composed of phycoerythrin (PE) followed by phycocyanin (PC) and allophycocyanin (APC). The dulse proteins showed slight ACE inhibitory activity, whereas the inhibitory activity was extremely enhanced by thermolysin hydrolysis. The ACE inhibitory activity of hydrolysates was hardly affected by additional pepsin, trypsin and chymotrypsin treatments. Nine ACE inhibitory peptides (YRD, AGGEY, VYRT, VDHY, IKGHY, LKNPG, LDY, LRY, FEQDWAS) were isolated from the hydrolysates by reversed-phase high-performance liquid chromatography (HPLC), and it was demonstrated that the synthetic peptide LRY (IC50: 0.044 μmol) has remarkably high ACE inhibitory activity. Then, we investigated the structural properties of dulse phycobiliproteins to discuss the origin of dulse ACE inhibitory peptides. Each dulse phycobiliprotein possesses α-subunit (Mw: 17,477–17,638) and β-subunit (Mw: 17,455–18,407). The sequences of YRD, AGGEY, VYRT, VDHY, LKNPG and LDY were detected in the primary structure of PE α-subunit, and the LDY also exists in the APC α- and β-subunits. In addition, the LRY sequence was found in the β-subunits of PE, PC and APC. From these results, it was suggested that the dulse ACE inhibitory peptides were derived from phycobiliproteins, especially PE. To make sure the deduction, we carried out additional experiment by using recombinant PE. We expressed the recombinant α- and β-subunits of PE (rPEα and rPEβ, respectively), and then prepared their peptides by thermolysin hydrolysis. As a result, these peptides showed high ACE inhibitory activities (rPEα: 94.4%; rPEβ: 87.0%). Therefore, we concluded that the original proteins of dulse ACE inhibitory peptides were phycobiliproteins.

Kappaphycus alvarezii (Doty) L. M. Liao, a red seaweed widely cultivated for carrageenan polysaccharide, is also a potential source of the valuable pigment phycoerythrin (PE). Therefore, this study aims to extract phycoerythrin from K. alvarezii , evaluate its antimicrobial, antioxidant, and anticancer activities, and identify its biomedical potential for future therapeutic applications. The protein content of phycoerythrin pigment extracted from K. alvarezii was found to be 69.84% and showed excellent antimicrobial activity against Klebsiella oxytoca and Proteus mirabilis , with a minimum inhibition zone of 11 mm. It showed significant in vitro antioxidant activity, as analyzed using total antioxidant, hydrogen peroxide scavenging, reducing power, DPPH, and ABTS assays. Further, the pigment exhibited potent cytotoxicity against a human lung cancer cell line, with an IC 50 value of 131.7 µg mL −1 . Furthermore, increasing concentration of phycoerythrin pigment decreased the cell proliferation and induced apoptosis, as confirmed by Annexin V/PI staining. Comprehensive characterization using FT-IR, HPLC, and GC-MS analysis revealed the nature of pigment and functional groups, highlighting its potential for biomedical applications. The molecular docking of K. alvarezii -derived compounds revealed significant binding affinities with 13 antibacterial target proteins. These results highlight the potential of K. alvarezii bioactive compounds as promising antibacterial agents. The phycoerythrin extract from K. alvarezii demonstrated potent antimicrobial, antioxidant, and anticancer properties, with significant cytotoxicity against lung cancer cells and confirmed apoptosis induction. Structural analysis revealed its bioactive composition, emphasizing its potential as a natural therapeutic agent. These findings support its potential application in the biomedical and pharmaceutical industries.

The objective of the present study was to identify peptides, based on active components of the red algae seaweed Pyropia yezoensis, able to inhibit the generation of reactive oxygen species (ROS), which is associated with aging and oxidative activities. Phycobilin, specific to red algae, covalently binds with water-soluble proteins. There are three types of pigment bound proteins, known as phycobiliproteins (PBPs): Phycoerythrin (PE), phycocyanin (PC) and allophycocyanin (APC). In the present study, PBPs reported previously to have antioxidant activities in P. yezoensis were identified and, based on these data, several peptides were synthesized (PBP 1-13) and their inhibition of ROS generation was examined. The existence of PBPs of each type, PE, PC and APC, was established in P. yezoensis and all were analyzed. In addition, PBP 1-2 and 7-9 peptides from PE were synthesized and showed antioxidant activities in HepG2 cells. In HepG2 cells, treatment with PBP2 reduced hydrogen peroxide-mediated oxidative stress and restored the expression of superoxide dismutase (SOD). Furthermore, phosphorylated nuclear factor erythroid-derived 2-like 2 (Nrf2) was elevated by PBP2 treatment. Overall, these results suggested that Nrf2-SOD pathways may be involved in the PBP2-mediated antioxidant effects. Therefore, from the investigations of P. yezoensis, several candidate peptides were identified with promising antioxidant and, potentially, anti-aging properties.

Arthrospira platensis (spirulina) is a cyanobacterium, which contains mainly two phycobiliproteins (PBP), i.e., C-phycocyanin (C-PC) and allophycocyanin (APC). In this study, PBP were hydrolyzed using trypsin, and the composition of the hydrolysate was characterized by HPLC-ESI-MS/MS. Furthermore, the potential anti-diabetic activity was assessed by using either biochemical or cellular techniques. Findings suggest that PBP peptides inhibit DPP-IV activity in vitro with a dose-response trend and an IC50 value falling in the range between 0.5 and 1.0 mg/mL. A lower inhibition of the DPP-IV activity expressed by Caco-2 cells was observed, which was explained by a secondary metabolic degradation exerted by the same cells.

Phycobiliproteins have gained increasing attention for their antidiabetic potential, yet the specific bioactive peptides and their targets and molecular mechanisms have remained unclear. In this study, four peptides with potential hypoglycemic activity were identified through virtual screening. Network pharmacology was employed to elucidate their hypoglycemic mechanism in the treatment of T2DM. A subsequent in vitro assay confirmed that the synthesized peptides, GR-5, SA-6, VF-6, and IR-7, exhibited significant inhibitory activity against α-glucosidase and DPP-IV. In insulin-resistant HepG2 models, all four peptides exhibited no cytotoxicity. Among them, GR-5 demonstrated the most promising therapeutic potential by remarkably enhancing cellular glucose consumption capacity. Furthermore, GR-5 administration substantially increased glycogen synthesis and enzymatic activities of hexokinase and pyruvate kinase with statistically significant improvements compared to the control groups. This study provides novel peptide candidates for T2DM treatment and validates an integrative strategy for targeted bioactive peptide discovery, advancing the development of algal protein-based therapeutics.

The nutritional and bioactive value of seaweeds is widely recognized, making them a valuable food source. To use seaweeds as food, drying and thermal treatments are required, but these treatments may have a negative impact on valuable bioactive compounds. In this study, the effects of dehydration, rehydration, and thermal treatment on the bioactive compounds (carotenoids, phycobiliproteins, total phenolic content (TPC), total flavonoids content (TFC)), antioxidant (ABTS and DPPH radical scavenging activities) and anti-Alzheimer’s (Acetylcholinesterase (AchE) inhibitory activities, and color properties of Porphyra umbilicalis and Porphyra linearis seaweeds were evaluated. The results revealed significant reductions in carotenoids, TPC, TFC, and antioxidant activities after the seaweeds’ processing, with differences observed between species. Thermal treatment led to the most pronounced reductions in bioactive compound contents and antioxidant activity. AchE inhibitory activity remained relatively high in all samples, with P. umbilicalis showing higher activity than P. linearis. Changes in color (ΔE) were significant after seaweeds’ dehydration, rehydration and thermal treatment, especially in P. umbilicalis. Overall, optimizing processing methods is crucial for preserving the bioactive compounds and biological activities of seaweeds, thus maximizing their potential as sustainable and nutritious food sources or as nutraceutical ingredients.

The study evaluated the effects of Arthrospira maxima phycobiliproteins (PBPs), rosiglitazone (RSG), and 17β-estradiol (E) on the differentiation process of 3T3-L1 cells and on their regulation of lipogenic and inflammatory gene expression at different stages of the process. The results showed that phycobiliproteins promoted cell proliferation after 24 h of treatment. Furthermore, for all three treatments, the regulation of the highest number of markers occurred on days 6 and 12 of differentiation, regardless of when the treatment was applied. Phycobiliproteins reduced lipid droplet accumulation on days 3, 6, 10, and 13 of the adipogenic process, while rosiglitazone showed no differences compared to the control. On day 6, both phycobiliproteins and rosiglitazone positively regulated Acc1 mRNA. Meanwhile, all three treatments negatively regulated Pparγ and C/ebpα. Phycobiliproteins and estradiol also negatively regulated Ucp1 and Glut4 mRNAs. Rosiglitazone and estradiol, on the other hand, negatively regulated Ppara and Il-6 mRNAs. By day 12, phycobiliproteins and rosiglitazone upregulated Pparγ mRNA and negatively regulated Tnfα and Il-1β. Additionally, phycobiliproteins and estradiol positively regulated Il-6 and negatively regulated Ppara, Ucp2, Acc1, and Glut4. Rosiglitazone and estradiol upregulate C/ebpα and Ucp1 mRNAs. The regulation exerted by phycobiliproteins on the mRNA expression of the studied markers was dependent on the phase of cell differentiation. The results of this study highlight that phycobiliproteins have an anti-adipogenic and anti-inflammatory effect by reducing the expression of adipogenic, lipogenic, and inflammatory genes in 3T3-L1 cells at different stages of the differentiation process.

Phycobiliproteins (PBPs), captivating water-soluble proteins found in cyanobacteria, red algae, and cryptophytes, continue to fascinate researchers and industries due to their unique properties and multifaceted applications. These proteins consist of chromophores called phycobilins (PBs), covalently linked to specific protein subunits. Major phycobiliproteins include phycocyanin (PC), allophycocyanin (APC), and phycoerythrin (PE), each distinguished by distinct absorption and emission spectra. Beyond their colorful properties, PBs exhibit a broad spectrum of biological activities, including antibacterial, antifungal, antiviral, and antidiabetic effects, making them valuable for pharmaceutical, biotechnological, and medical purposes. The extraction and purification methods for PBs have been optimized to enhance their bioavailability and stability, opening new avenues for industrial production. For this review, a comprehensive literature search was conducted using scientific databases such as PubMed, Scopus, and Web of Science, prioritizing peer-reviewed articles published between 2000 and 2025, with an emphasis on recent advances from the last five years, using keywords such as “phycobiliproteins”, “phycobilins”, “bioactivities”, “therapeutic applications”, and “industrial use”. Studies were selected based on their relevance to the biological, technological, and pharmacological applications of PBPs and PBs. This review explores the diverse applications of PBs in therapeutic, diagnostic, and environmental fields, highlighting their potential as natural alternatives in the treatment of various diseases. The future perspectives for PBs focus on their incorporation into innovative drug delivery systems, biocompatible materials, and functional foods, presenting exciting opportunities for advancing human health and well-being.

Cadmium (Cd) is known for its many toxic effects on male population such as hypogonadism and fertility difficulties, which are oftenly associated with oxidative stress. As beneficial food, Spirulina (Sp) has been proved efficient against the heavy metal toxicity. This capacity can be associated with its phycobiliproteins (PBP). In this study, the capability of PBP and Sp to treat Cd-induced oxidative damage on the testes and spermatozoa was considered. CD-1 strain mice were orally treated with either Sp or PBP for 10 days prior to single-dose Cd challenge. Sperm quality determinations and testicle histology analysis were performed. Testosterone on serum was measured using enzyme-linked immunosorbent assay (ELISA). Oxidative damage was determined. Antioxidant enzyme activity was analyzed by measuring the activity of super oxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GpX). The motility and viability of sperm decrease with Cd and improve with PBP and Sp, as the acrosomal reaction (AR) is diminished by PBPs. Testosterone levels decrease due to Cd, and only Sp maintains elevated levels. Cd increases the production of malondialdehyde in the spermatozoa, but not in testes; this production of malondialdehyde in the spermatozoa decreases in the presence of PBP. ROS only decreases with Cd, FBP, and Sp at high concentrations. Advanced oxidative protein products (AOPP) decrease with Cd and PBPs. Cat and GpX increase their activity with Cd and are altered by FBP. Cd produces vascular alterations testes. Within the seminiferous tubule, it produces areas of necrosis and apoptosis, which improve with PBPs and Sp. PBPs have a strong antioxidant activity as they show protective properties against Cd oxidative–induced toxicity on testes and sperm.

Alzheimer’s disease (AD) is characterized by β-amyloid plaques, neurofibrillary tangles, neuroinflammation, and oxidative stress—pathological features that pose significant challenges for the development of therapeutic interventions. Given these challenges, this review comprehensively evaluates the neuroprotective mechanisms of bioactive compounds derived from red algae, including polysaccharides and phycobiliproteins, which are considered a promising source of natural therapeutics for AD. Red algal constituents exhibit neuroprotective activities through multiple mechanisms. Sulfated polysaccharides (e.g., carrageenan, porphyran) suppress NF-κB-mediated neuroinflammation, modulate mitochondrial function, and enhance brain-derived neurotrophic factor (BDNF) expression. Phycobiliproteins (phycoerythrin, phycocyanin) and peptides derived from their degradation scavenge reactive oxygen species (ROS) and activate antioxidant pathways (e.g., Nrf2/HO-1), thus mitigating oxidative damage. Carotenoids (lutein, zeaxanthin) improve cognitive function through the inhibition of acetylcholinesterase and pro-inflammatory cytokines (TNF-α, IL-1β), while phenolic compounds (bromophenols, diphlorethol) provide protection by targeting multiple pathways involved in dopaminergic system modulation and Nrf2 pathway activation. Emerging extraction technologies—including microwave- and enzyme-assisted methods—have been shown to optimize the yield and maintain the bioactivity of these compounds. However, the precise identification of molecular targets and the standardization of extraction techniques remain critical research priorities. Overall, red algae-derived compounds hold significant potential for multi-mechanism AD interventions, providing novel insights for the development of therapeutic strategies with low toxicity.