Search Results (1,131)

Background: High-dose melphalan 140–200 mg/m² (HDM) with autologous stem cell transplant (ASCT) is standard first-line treatment in multiple myeloma (MM), yet standard BSA-based dosing results in wide variation in systemic exposure (AUC). We developed a pharmacokinetic (PK)-guided dosing strategy using a 100 mg/m² first dose, enabling real-time PK assessment and individualized adjustment for the second dose. We report final results of Phase A of our multi-center Phase 1 trial (NCT04483206, MyMel) evaluating feasibility and accuracy of this personalized approach. Methods: Patients received melphalan 100 mg/m² on Day −3, and seven PK samples were collected and shipped overnight for LC-MS/MS analysis. Real-time AUC estimation using noncompartmental analysis (NCA) guided Day −1 dosing to achieve pre-specified AUC targets (13.5 or 14.5 mg × h/L). For comparison, post hoc Bayesian estimation using a nonlinear mixed effects (NLME) model was performed. Sparse sampling designs were evaluated using NONMEM. Results: All 20 patients successfully received PK-guided dosing, with Day −1 doses determined within 48 h. PK-guided dosing reduced AUC variability (CV 4.20–5.62%), with 19 of 20 achieving AUCs within ±10% of the target, compared to what would have been achieved by BSA dosing (CV 9.74–15.34%). NLME improved accuracy, particularly in patients with missing samples, and maintained performance using only four PK time points. Conclusions: This study demonstrates that PK-guided dosing is accurate and feasible with HDM-ASCT. NLME enhances accuracy and enables simplified sampling. Phase B will identify maximum tolerated systemic exposure of seven additional AUC cohorts using the NLME model and a four-sample design. Full article

To fully explore the metabolites of the mangrove endophytic fungus Penicillium janthinellum HDN13-309, which can produce Epipolythiodioxopiperazine (ETP) compounds with noteworthy anti-tumor activities, HPLC-MS analysis was applied, and five new gliovirin-like alkaloids, penicisulfuranols G–K (1–5), were target-directed acquired. Furthermore, penicisulfuranols G (1) and H (2) were distinguished by a double bond between C-5/C-6 and ortho-hydroxylation of C-7/C-8 on the 1,2-oxazadecaline moiety. Their structures, including absolute configurations, were elucidated based on NMR spectroscopy, ECD measurements, and high-resolution mass spectrometry, as well as by comparison with the literature. Penicisulfuranols I–K (3–5) showed promising cytotoxicity against four tumor cell lines (HCT116, HeLa, HL-60, and K562) with IC₅₀ values ranging from 0.1 to 9.9 μM. Full article

Background/Objectives: The human cathelicidin LL-37 (37 residues; net charge +6) couples broad-spectrum antimicrobial activity with immunomodulatory function, but rapid proteolysis and peptidylarginine deiminase (PAD)-mediated citrullination limit its therapeutic use. We aimed to enhance enzymatic stability and to test whether substitution with 2,3-diaminopropionic acid (Dap) building blocks bearing an oxa-acid spacer (DAPEG) shifts the functional profile of the LL-37 scaffold. Methods: Six LL-37 analogs were synthesized using Fmoc/tBu solid-phase peptide synthesis, replacing all five arginine, all six lysine, or three isoleucine residues with Dap bearing a one- or two-unit oxa-acid spacer. Identity, purity and secondary structure were assessed via mass spectrometry, ultra-performance liquid chromatography and circular dichroism. Proteolytic stability against human proteinase 3 (PR3), resistance to PAD2/PAD4 citrullination, DNA binding (dynamic light scattering), antibacterial activity, MTT cytotoxicity, and lipopolysaccharide-induced degranulation (PR3 and myeloperoxidase) in differentiated HL-60 cells were evaluated. Results: Proteolytic stability against PR3 increased 5.7-fold for the arginine-substituted Dap(GO1) analog, and both arginine analogs resisted PAD2- and PAD4-mediated citrullination, with Dap(GO2) being the most resistant. DNA binding was qualitatively retained, although dynamic light scattering showed weaker complex compaction for lysine analogs. All six analogs lost direct antibacterial activity and were non-cytotoxic at 1–10 µM. In differentiated HL-60 cells, the lysine-substituted Dap(O1) and Dap(O2) analogs suppressed lipopolysaccharide-induced secretion of both PR3 and myeloperoxidase from azurophilic granules, whereas isoleucine analogs were suppressed partially and arginine analogs behaved like native LL-37. Conclusions: The DAPEG framework shifts LL-37 from microbicidal toward degranulation-suppressive activity, providing a modular route to tune cathelicidin function. The intracellular mechanism (TLR4/FPR2 engagement, cytokine signaling) was not assayed. Full article

Background: Pathogenic variants in the PPP1R12A gene have been associated with a malformation syndrome involving the brain and the genitourinary systems (GUBS, MIM #618820). To date, neither hearing loss (HL) nor inner ear malformations have been reported in affected individuals, and these features are therefore not currently regarded as part of the PPP1R12A-related phenotype. Moreover, functional evidence supporting the pathogenicity of several reported variants remains limited. Methods: We investigated a 12.5-year-old patient presenting with profound bilateral sensorineural hearing loss associated with inner ear malformations, genitourinary and central nervous system abnormalities. The patient underwent comprehensive clinical, audiological and radiological assessments, followed by genetic testing via trio-based whole-exome sequencing (WES). The molecular consequences of the identified variant were evaluated through minigene splicing assay and RT–PCR analysis on RNA extracted from peripheral blood cells. Results: WES identified a novel heterozygous splicing variant (c.792+3A>C) in the PPP1R12A gene (NM_002480.3). Functional studies demonstrated that this variant causes complete skipping of exon 5, resulting in a frameshift and the introduction of a premature termination codon. RT–PCR analysis confirmed the presence of the alternatively spliced transcript lacking exon 5. In addition, an extensive review of the literature indicated that no clear genotype–phenotype correlation has yet been established for PPP1R12A-related disorders and, whereas the majority of previously reported patients share brain and genitourinary malformations our patient additionally presented with profound bilateral sensorineural HL and inner ear malformations. Conclusions: Our findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and we further propose that HL and inner ear malformations may represent novel features associated with this clinical spectrum. Moreover, our study underscores the importance of functional studies for accurately defining the molecular consequences of novel variants and establishing appropriate clinical correlations. Full article

Background/Objectives: Chronic myeloid leukemia (CML) is a hematological malignancy driven by the constitutively active BCR-ABL1 fusion protein. Although current ABL1 tyrosine kinase inhibitors (TKIs) have improved CML management, resistance remains a major challenge, highlighting the need for novel therapeutic strategies. Methods: A chalcone derivative containing naphthalene and toluene moieties (A) was synthesized from 2-acetonaphthone and p-tolualdehyde and subsequently converted into a novel 4,5-dihydro-1H-pyrazole-1-carbothioamide derivative (B) through reaction with thiosemicarbazide. The cytotoxicity of compounds A and B against K562 CML cells was evaluated using the MTT assay. The active compound was further investigated for cytotoxic selectivity using HL-60 acute myeloid leukemia (AML) cells and healthy PBMCs. Apoptotic effects in K562 cells were analyzed using Annexin V/ethidium homodimer staining, whereas ABL1 inhibitory activity was determined using the ADP-Glo kinase assay. The potential interaction between the active compound and ABL1 was assessed by molecular docking analysis. Results: Compound B displayed potent cytotoxic activity against K562 cells with an IC₅₀ value of 6.92 ± 1.14 µM and demonstrated selectivity toward leukemic cells over PBMCs (SI = 5.4). Treatment with compound B markedly induced apoptosis in K562 cells. In addition, compound B inhibited ABL1 activity in a concentration-dependent manner. Molecular docking studies revealed a favorable binding orientation within the ATP-binding pocket of ABL1. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) analysis predicted favorable pharmacokinetic properties for compound B. Conclusions: These findings demonstrate that compound B possesses cytotoxic, pro-apoptotic, and ABL1 inhibitory activities against CML cells and may serve as a promising lead structure for the development of novel therapeutic agents targeting CML. Full article

Tick-borne bacterial infections such as those caused by Anaplasma phagocytophilum are difficult to diagnose, particularly at early stages, because they rely on specialized laboratory tests. Dielectric-based measurements provide a label-free way to probe cellular state and may offer useful information. In this study, we explored whether A. phagocytophilum-infected and uninfected HL-60 human promyelocytic leukemia cells can be distinguished using dielectric measurements collected under controlled in vitro conditions. Measurements were performed at two medium conductivities (100 and 300 µS/cm), and three dielectric properties were examined: cytoplasmic conductivity, specific membrane conductance, and specific membrane capacitance. We used exploratory analysis, statistical tests, and interpretable linear classifiers, with performance evaluated using leave-one-out cross-validation. Membrane-related properties, especially specific membrane conductance, showed the clearest separation between infection states and were consistently the most informative across models. Both classification performance and effect sizes were stronger at the higher medium conductivity condition. These results are encouraging, but because the sample size was small and consisted only of technical replicates, they should be interpreted as preliminary measurement-level evidence. This study is intended as a pilot and supports further work with larger datasets, additional cell types, and broader experimental conditions. Full article

Background/Objectives: The clinical application of the potent antitumor alkaloid camptothecin is severely limited by its high systemic toxicity, poor solubility, and rapid inactivation. This study aimed to design, synthesize, and evaluate a novel series of camptothecin–lipid conjugates where natural steroids and triterpenoids serve as lipophilic carriers to enhance cellular penetration and mitigate cardiotoxicity. Herein, we implemented an endogenous targeting strategy by conjugating camptothecin with natural steroids and triterpenoids, which serve as biomimetic lipophilic vectors to achieve tumor-selective intracellular delivery. Methods: Eleven novel camptothecin-based hybrids linked via succinic acid or ethylene glycol spacers were synthesized and characterized. Their in vitro cytotoxicity was evaluated against eight cancer cell lines of varied embryologic origin (Jurkat, HCT 116, A549, HL60, K562, HeLa, HEK293, and Fibroblasts). Cell cycle distribution, apoptosis induction, and topoisomerase I inhibitory activity were assessed using flow cytometry and enzyme assays. In silico pharmacokinetic profiling, including P-glycoprotein interaction and cardiotoxicity mitigation, was substantiated via ADME algorithms. Results: Among the series, compounds 12 (cholestanol conjugate) and 26 (betulin derivative) emerged as the primary lead candidates based on an optimal composite of submicromolar cytotoxicity, exceptional tumor selectivity indices (up to 7.0 for 12), and active topoisomerase I inhibition. Compounds 11–14 generally shared prominent S-phase cell cycle arrest, while the lead hybrids 12 and 26 successfully combined high apoptotic triggering with favorable in silico ADME safety profiling, including eliminated cardiotoxicity for the structural analogs. Conclusions: The integration of steroidal and triterpenoid pharmacophores via strategic spacers provides a reliable foundation for developing targeted, low-toxicity camptothecin–lipid conjugates with optimized safety profiles for cancer therapy. Full article

Background and Objectives: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is characterized by type 2 inflammation, marked eosinophil infiltration, and enhanced epithelial–mesenchymal transition (EMT). Although interleukin-5 (IL-5) is central to eosinophil differentiation and activation, its role in EMT in human nasal epithelial cells (HNECs) remains unclear. This study aimed to elucidate the contribution of IL-5Rα/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling in eosinophils in EMT in ECRSwNP. Materials and Methods: Nasal mucosal tissues from control and ECRSwNP or non-ECRSwNP group patients (n = 12 each) were analyzed for type 2 cytokine, EMT marker, and IL-5Rα/JAK2/STAT5 axis component levels using Western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. HL-60 cells were differentiated into eosinophil-like cells using butyric acid and stimulated with IL-5, and HNECs were co-cultured with undifferentiated, differentiated, or IL-5-activated differentiated HL-60 cells. EMT induction and migration were assessed using immunofluorescence, wound-healing assays, and Western blotting. IL-5RA, JAK2, or STAT5 was silenced using small interfering RNA to determine pathway dependency. Results: ECRSwNP tissues showed elevated type 2 cytokine and EMT marker expression and enhanced IL-5Rα/JAK2/STAT5 pathway activation. Co-culture with IL-5-activated differentiated HL-60 cells induced EMT in HNECs, evidenced by decreased E-cadherin and zonula occludens-1, increased N-cadherin and vimentin levels, and enhanced migration. Moreover, silencing IL-5RA, JAK2, or STAT5 significantly attenuated these effects. Conclusions: IL-5-activated IL-5Rα/JAK2/STAT5 signaling in eosinophils may contribute to EMT in HNECs. Thus, this pathway could be a potential therapeutic target for tissue remodeling and polyp formation in type 2 chronic rhinosinusitis. Full article

The clinical success of cisplatin has significantly spurred the exploration of new organometallic complexes in oncology. In this quest, repurposing of auranofin as an anticancer agent has diverted the research interest from platinum to gold complexes, as gold offers unique chemical features; among them, thioredoxin reductase (TrxR) inhibition is one of the most extensively studied anticancer pathways. In this study, we have compiled the major ligand modifications reported for gold(I) complexes and categorized them into various groups, which include sulfur-based ligands, nitrogen-containing heterocyclic ligands, carbon-derived ligands, and N-heterocyclic carbene-based ligands. Also, a few structurally distinct ligands, including propargyl-, allene-, tricarbene-, and urea-functionalized NHC frameworks, have further extended structural diversity and functional potential. The in vitro evaluation of these newly synthesized gold complexes against various cancer cell lines exhibited enhanced biological potential compared to conventional metal complexes. Comparative evaluation of the reported cytotoxicity data revealed distinct structure–activity relationships among different ligand classes, with phosphine-carbon donor and bis-NHC frameworks emerging as the most promising ligand for achieving potent anticancer activity, highlighting the critical role of ligand design in modulating anticancer activity. In addition, the use of bioactive pharmacophores derived from natural products and active pharmaceuticals has emerged as a promising design strategy for developing multitarget gold(I) complexes with enhanced therapeutic efficacy. Among the reviewed compounds, complex 68 containing a bis-NHC ligand exhibited the highest potency against HL-60 leukemia cells (GI₅₀ = 0.017 μM), while complex 49 bearing a carbon-donor ligand demonstrated remarkable activity against A549 lung cancer cells (IC₅₀ = 0.02 μM). Several other gold(I) complexes also exhibited submicromolar activity against diverse cancer cell lines, further emphasizing the importance of rational ligand engineering in enhancing anticancer efficacy. Collectively, gold(I) complexes have emerged as a promising class of anticancer agents, and the comparative evaluation presented herein provides a valuable framework for identifying potent ligand scaffolds and guiding the rational development of next-generation gold-based therapeutics. Future advances in ligand engineering may facilitate targeted drug delivery, controlled release, and multi-mechanistic therapeutic strategies to overcome toxicity and drug resistance while enhancing therapeutic efficacy. Full article

With the introduction of Navarixin in clinical trials, the role of squaric acid derivatives as bioisosteres gained popularity. Because of their distinctive electronic properties and hydrogen-bonding capacity, these compounds hold considerable promise for medicinal chemistry applications. In this study, a series of novel furan- and thiophene-containing squaric acid derivatives was synthesized via base-catalyzed nucleophilic substitution and characterized by spectroscopic techniques. The structures of three compounds were additionally confirmed by X-ray crystallography. Density functional theory calculations showed good agreement with the experimental vibrational spectra. In silico evaluation predicted favorable drug-like characteristics, including compliance with Lipinski’s rule of five and high gastrointestinal absorption. The cytotoxic activity of the synthesized compounds was assessed against HeLa, HT-29, HL-60, A-549, and MCF-7 cancer cell lines, as well as the non-cancerous CCL-1 cell line. Several derivatives displayed moderate to strong antiproliferative activity with selectivity toward malignant cells. Compound 3d exhibited the most pronounced improvement (five-fold) over Navarixin in HL-60 cells 5.81 µM, while compounds 3a and 3c demonstrated superior potency and selectivity in A-549 cells (10.33 µM and 9.65 µM). These findings identify squaric acid derivatives as promising candidates for further anticancer drug development and structure–activity relationship studies. Full article

In this study, an exploratory transcriptomic investigation was conducted to evaluate the feasibility of using feather transcriptomics to detect sex differences and gene responses to physiological changes in chickens. Feathers represent a promising non-invasive biological source of RNA, as the feather pulp of growing feathers contains living cells capable of active transcription. Growing feathers were collected from 150-day-old male and female chickens (Bionda Piemontese, a slow-growing breed) raised under a free-range system and fed two finisher diets differing in lipid content: low-lipid (LL, ether extract 3.6%) and high-lipid (HL, ether extract 9.3%) diets. RNA was extracted from feather pulp, and 12 pools were subjected to whole RNA-Seq analysis. The study was designed as 2 × 2 factorial experiments investigating the effects of diet and sex on gene expression. A total of 17,360 transcripts were detected and used for downstream analyses. Differential gene expression and functional enrichment analyses were performed. The main effects of diet and sex were estimated with an additive design using the DEseq2 package, while for the sex-specific diet analyses, subgroup comparisons were conducted on the RaNA-Seq platform. The analysis of the main effect of diet reveals that three genes associated with ether lipid metabolism (PLA2G10, PLA2G4F, and ENPP6) were upregulated in chickens fed the HL diet. In roosters, HL feeding significantly altered the expression of APOA1 and SLC27A4, suggesting an effect on lipid transport and metabolic regulation within the PPAR signaling pathway. In contrast, hens showed differential expression primarily in pathways related to apelin signaling, extracellular matrix remodeling, and cardiovascular function, rather than classical lipid metabolism pathways; additionally, gene set enrichment analysis indicated a limited enrichment of linoleic acid metabolism, suggesting secondary involvement of lipid metabolic processes. These findings are consistent with those in the literature reporting sex-related differences between males and females. The results further suggest that transcriptomic responses to dietary lipid supplementation can be investigated through the expression of selected candidate genes in feather pulp. Among the genes identified, PLA2G10, PLA2G4F, ENPP6, APOA1, and SLC27A4 emerged as potential molecular markers associated with dietary treatment, and the importance of sex-dependent transcriptional responses was highlighted. In conclusion, this study demonstrates the potential of feather pulp as a viable source of RNA for transcriptomic analyses in live chickens, providing a minimally invasive alternative to conventional tissue sampling. These preliminary results also support the hypothesis that feathers represent a practical and ethically favorable tissue for future nutrigenomic and genetic improvement studies, ultimately supporting more sustainable poultry production. Full article

Background/Objectives: Myocardial microcirculatory dysfunction is a critical pathological feature of cardiovascular diseases, closely associated with inflammation, oxidative stress, and excessive neutrophil activation. Neutrophil extracellular traps (NETs) serve as crucial mediators of myocardial microvascular inflammatory injury. Dalbergia odorifera volatile oil (DOVO) demonstrates anti-inflammatory and antioxidant properties; however, its protective role against myocardial microcirculatory damage and its regulatory effect on NET formation remain inadequately characterized. This study investigates the protective effects of DOVO on myocardial microcirculatory disturbances and elucidates the underlying mechanisms related to NETs. Methods: A rat model of myocardial microcirculatory dysfunction was established through polyethylene microsphere injection, and an in vitro neutrophil inflammation model was generated using differentiated HL-60 cells. DOVO was administered at various doses both in vivo and in vitro, and hemodynamics, inflammatory cytokines, oxidative stress, and NET-related markers, including MPO and CitH3, were analyzed. Results: DOVO dose-dependently ameliorated microcirculatory impairment, hemodynamic disorders, inflammation, and oxidative stress in rats, significantly suppressing NET formation. In differentiated HL-60 cells, DOVO similarly reduced inflammatory gene expression and inhibited LPS-induced NETs production by downregulating MPO and CitH3. Conclusions: DOVO suggests a protective effect against myocardial microcirculatory injury by inhibiting oxidative stress, inflammatory responses, and subsequent NET formation. These findings elucidate a novel mechanism by which DOVO alleviates microcirculation-related cardiac damage and provide a theoretical basis for its application in cardiovascular injury. Full article

In Argentina, a high incidence of EBV-associated lymphomas was demonstrated in young children. Natural killer (NK) cells, particularly, IFN-γ-producing CD56bright NK cells, have been reported to play a key role in asymptomatic EBV infection in children, restricting viral-mediated transformation. In order to analyze NK cell characteristics in children with primary and persistent EBV infection, along with EBV+ Hodgkin lymphoma (HL) from Argentina, a cohort of EBV-infected pediatric patients was analyzed. A scarcity of CD56+ cells, as an indirect marker of NK cells, across all tonsillar samples and pediatric classical Hodgkin lymphoma cases was observed, with no significant differences according to EBV status. In primary infection, CD56+ cells showed a positive correlation with IFNγ+ cells, suggesting a role in early antiviral responses. Flow cytometry revealed an increased proportion of CD56bright NK cells in EBV-infected children, particularly in cases expressing latency II/III antigens. A significantly higher IFN-γ production was observed in CD56bright cells in children with primary infection compared with healthy carriers, along with an inverse correlation between IFN-γ production and CD56bright cells in healthy carriers. These findings suggest that NK cells may contribute to immune control predominantly during primary infection, whereas their role appears limited in healthy carriers and in EBV-associated Hodgkin lymphoma. Full article

Background/Objectives: Chronic myeloid leukemia (CML) is primarily associated with the BCR:ABL1 fusion protein. Although tyrosine kinase inhibitors (TKIs) have markedly enhanced treatment outcomes, the development of agents with improved therapeutic characteristics remains necessary. The present work focused on the synthesis of a new series of thiazolone derivatives (F1-11) and the assessment of their anti-CML activity through inhibition of ABL tyrosine kinase (TK). Methods: The designed compounds were prepared through a multistep synthetic pathway involving the formation of a new chalcone intermediate (A), synthesis of a new pyrazoline carbothioamide intermediate (B), and cyclization with different aldehydes to produce the target new thiazolone derivatives (F1-11). Cytotoxic effects were investigated against K562 CML cells using the MTT assay. The lead compound was additionally evaluated in HL-60 AML cells and normal PBMCs. Apoptotic induction was analyzed using Annexin V/ethidium homodimer staining, whereas ABL TK inhibitory activity was measured through the ADP-Glo assay. Molecular docking studies were conducted to explore ligand interactions within the ATP-binding domain of ABL TK. Results: Among the synthesized molecules, F-4 demonstrated the strongest activity against K562 cells with an IC₅₀ value of 6.85 µM, close to that observed for imatinib (IC₅₀ = 5.20 µM). The compound showed reduced cytotoxicity toward HL-60 cells (IC₅₀ = 33.44 µM) and exhibited favorable selectivity toward PBMCs (SI = 13). Apoptosis studies revealed 51% early apoptotic cells and 43% late apoptotic cells following treatment. In the kinase assay, F-4 inhibited ABL TK activity by 39% at 10 µM and by 70% at 100 µM. Docking simulations suggested interactions with residues His361 and Asp381 in addition to nearby hydrophobic amino acids, although the interaction network was less extensive than that of imatinib. Conclusions: The findings identify F-4 as a promising new thiazolone-derived scaffold with selective anti-CML activity and notable ABL TK inhibitory potential. Additional structural optimization may further enhance its binding characteristics and therapeutic efficacy. Full article

This study assessed the effects of different intensities of broad-spectrum white LED light (PAR range: 415–748 nm) on growth, fucoxanthin accumulation, and fatty acid composition of Isochrysis galbana. This study classified light intensity into three categories based on the white LED light source: high (HL, 150 μmol·m⁻²·s⁻¹), medium (ML, 80 μmol·m⁻²·s⁻¹), and low (LL, 30 μmol·m⁻²·s⁻¹). The results showed that biomass concentration was optimized under high light intensity (HL, 150 μmol·m⁻²·s⁻¹), whereas low light (LL, 30 μmol·m⁻²·s⁻¹) yielded the highest fucoxanthin concentration (71.15 mg/L on day 12) and the only positive volumetric fucoxanthin productivity (3.14 mg/L/d) among the three treatments tested. The results further showed that low light (LL, 30 μmol·m⁻²·s⁻¹) produced maximum cell density (10.08 × 10⁶ cells/mL) and the most polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constituted 1.93% and 22.47% of total fatty acids, respectively. This study demonstrates that low-intensity (LL, 30 μmol·m⁻²·s⁻¹) white LED light supports the maximum co-production of valuable metabolites in I. galbana, establishing a scientific basis for scaling up I. galbana cultivation for nutraceutical and aquafeed applications. Full article