Carmela Gallo

Marine mollusks of the order Nudibranchia produce a wide array of secondary metabolites that play key roles in predator-prey interactions and often exhibit remarkable bioactivity. In this study, a chemical investigation of the Mediterranean aeolid nudibranchs Cratena peregrina and Paraflabellina ischitana led to the isolation and characterization of a novel oxylipin, designated cratenin (1). This unique metabolite shows an unusual alkylated monosubstituted tetrahydrofuran (THF) moiety, a structural feature rarely encountered among marine natural products. The planar structure of 1 was fully elucidated by high-resolution mass spectrometry (HRMS) and comprehensive 1D and 2D NMR spectroscopy, while the absolute configuration of the substituted THF ring was rigorously established by chemical degradation, derivatization, and NMR-based stereochemical comparison with known diasteromeric derivatives of (tetrahydrofuran-2-yl)methanol. The co-occurrence of cratenin (1) in the hydrozoan Eudendrium racemosum, a known prey of C. peregrina and other aeolid nudibranchs, strongly suggests its role as a semiochemical which mediates predator-prey interactions. The proposed biosynthetic origin of cratenin (1) from algal docosahexaenoic acid (DHA) further corroborates the hypothesis of dietary acquisition and provides compelling molecular evidence for kleptopredation, a sophisticated foraging behavior where nudibranchs consume prey that has recently ingested phytoplankton. In this view, this study reveals a clear metabolic and ecological link connecting phytoplankton, hydrozoans, and nudibranchs, underscoring the pivotal role of lipid-derived natural products in shaping chemical communication and interphyletic trophic interactions involving opisthobranchs.

Background: Microglial dysfunction has emerged as a critical factor in the Alzheimer’s Disease (AD), with innate immune dysregulation driving pathological progression. This growing understanding has shifted attention toward the therapeutic modulation of glial response as a means to restore immune balance and promote neuronal resilience. Increasing attention has also focused on small-molecules capable of reprogramming microglia toward a reparative, surveillance-competent phenotype that enhances Amyloid-β (Aβ) clearance while limiting detrimental neuroinflammation. In this context, we previously reported that Sulfavant A (SULF A), a novel synthetic sulfolipid, binds to Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and activates myeloid cells without inducing inflammatory hallmarks. Methods: The immunomodulatory properties of SULF A were characterized using biochemical, molecular, and cell biological approaches in primary murine microglia. The small modulatory molecule SULF A was synthetically produced in our laboratory. Functional assays included quantitative analyses of phagocytosis using standard beads and fluorescently labeled Aβ peptides, designed and synthesized considering tag emission and fiber aggregation. Aβ aggregation was characterized using biophysical and biochemical methods to ensure well-defined assemblies in microglial assays. To assess translational relevance, SULF A was evaluated at two distinct time points, before and after Aβ plaque deposition, in Tg2576 transgenic mice, a well-established AD model, to determine its neuroprotective potential and therapeutic efficacy. Results: We demonstrate that the small-molecule TREM2 ligand SULF A functions as an immunomodulator that reprograms microglia toward a reparative phenotype. It promotes a ramified and polarized microglial morphology associated with enhanced cellular motility, phagocytic capacity and clearance of neurotoxic Aβ peptides. SULF A upregulates arginase expression, downregulates inducible Nitric Oxide Synthase (iNOS), and redirects microglial metabolism toward tissue-protective functions. This phenotypic shift is characterized by increased TREM2 turnover and upregulation of CD68 and CCL2, without triggering classical inflammatory hallmarks. In vivo, SULF A enhances plaque‑associated microglial recruitment, reduces plaque burden, preserves midbrain dopaminergic neurons, and improves cognitive and motivational performance in Tg2576 mice. Conclusions: We propose that SULF A is a promising therapeutic small molecule that restores microglial homeostasis via an inflammation-sparing mechanism. It enhances amyloid clearance, preserves vulnerable neurons, and improves cognitive function in vivo. These findings support SULF A as a disease-modifying approach that extends beyond conventional plaque-targeting strategies in AD.

Professional antigen-presenting cells (APCs) represent a crucial link between the innate and the adaptive immune response. APCs express specific surface receptors which are primarily involved in “non-self” and/or “self” ligand recognition. Upon ligand binding, these receptors can trigger cell signalling leading to the production of pro-inflammatory cytokines, chemokines and Type 1 interferons, supporting antimicrobial and inflammatory responses. Recently, two major families of receptors, C-type lectin receptors and immunoglobulin receptors, are emerging as potential therapeutic targets to activate and modulate immune system through different intracellular signalling motifs upon binding with endogenous and exogenous ligands. The chemical characterization of the molecular determinants necessary for the receptors/ligands binding promotes the design and optimization of small molecules crucial for the comprehension of biological functions and for the therapeutic treatment of specific receptor-associated disorders. This review focuses on the description of these ligands together with their biological evaluation and their impact on the modulation of the immune response.

Vanadium compounds are known for their antidiabetic properties due to their ability to interfere with numerous mechanisms that lead to the decrease of blood glucose levels. Although some of these compounds have reached clinical trials and have the advantage of being orally administrable, no vanadium-containing drugs are currently available on the market, primarily due to the high doses required, which can lead intestinal and renal problems in case of long-term treatments. In this study, plant extracts obtained from olive leaves (Olea europaea L.) were combined with vanadium complexes with established antidiabetic activity with the aim of reducing their metal toxicity and, at the same time, amplifying their hypoglycemic action. The extracts were characterized by chromatographic and spectroscopic methods showing a composition rich in polyphenols and a high antioxidant activity. Formulations containing a vanadium complex (bis(maltolato)oxidovanadium(IV), BMOV, or bis(picolinato)oxidovanadium(IV), BPOV) mixed with different amount of olive leaves extract were tested in vitro to evaluate intestinal toxicity and hypoglycemic activity. The results demonstrated that the plant extracts are generally non-toxic toward human colon fibroblast in the whole range of tested concentrations and some of them are particularly effective in reducing the toxicity of the two vanadium compounds. Further in vitro tests conducted on differentiated human adipocyte cell lines revealed a significant increase in glucose uptake following treatment with the mixed formulations, compared to the effect of the individual components, indicating a synergistic effect. Immunocytochemical assays suggested that the translocation of GLUT4 transporter can be involved in the mechanism of action.

Marine sponges represent a good source of natural metabolites for biotechnological applications in the pharmacological, cosmeceutical, and nutraceutical fields. In the present work, we analyzed the biotechnological potential of the alien species Haliclona (Halichoclona) vansoesti de Weerdt, de Kluijver & Gomez, 1999, previously collected in the Mediterranean Sea (Faro Lake, Sicily). The bioactivity and chemical content of this species has never been investigated, and information in the literature on its Caribbean counterpart is scarce. We show that an enriched extract of H. vansoesti induced cell death in human melanoma cells with an IC₅₀ value of 36.36 µg mL⁻¹, by (i) triggering a pro-inflammatory response, (ii) activating extrinsic apoptosis mediated by tumor necrosis factor receptors triggering the mitochondrial apoptosis via the involvement of Bcl-2 proteins and caspase 9, and (iii) inducing a significant reduction in several proteins promoting human angiogenesis. Through orthogonal SPE fractionations, we identified two active sphingoid-based lipid classes, also characterized by nuclear magnetic resonance and mass spectrometry, as the main components of two active fractions. Overall, our findings provide the first evaluation of the anti-cancer potential of polar lipids isolated from the marine sponge H. (Halichoclona) vansoesti, which may lead to new lead compounds with biotechnological applications in the pharmaceutical field.

Recently, we described synthetic sulfolipids named Sulfavants as a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton. The members of this family, Sulfavant A (1), Sulfavant R (2), and Sulfavant S (3), showed important effects on triggering receptor expressed on myeloid cells 2 (TREM2)-induced differentiation and maturation of human dendritic cells (hDC), through a novel cell mechanism underlying the regulation of the immune response. As these molecules are involved in biological TREM2-mediated processes crucial for cell survival, here, we report the synthesis and application of a fluorescent analogue of Sulfavant A bearing the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene moiety (Me₄-BODIPY). The fluorescent derivative, named PB-SULF A (4), preserving the biological activity of Sulfavants, opens the way to chemical biology and cell biology experiments to better understand the interactions with cellular and in vivo organ targets and to improve our comprehension of complex molecular mechanisms underlying the not fully understood ligand-induced TREM2 activity.

Marine invertebrates are a traditional source of natural products with relevant biological properties. Tunicates are soft-bodied, solitary or colonial, sessile organisms that provide compounds unique in their structure and activity. The aim of this work was to investigate the chemical composition of the ascidian Cystodytes dellechiajei, selected on the basis of a positive result in biological screening for ligands of relevant receptors of the innate immune system, including TLR2, TLR4, dectin-1b, and TREM2. Bioassay-guided screening of this tunicate extract yielded two known pyridoacridine alkaloids, shermilamine B (1) and N-deacetylshermilamine B (2), and a family of methyl-branched cerebrosides (3). Compounds 2 and 3 showed selective binding to TREM2 in a dose-dependent manner. N-deacetylshermilamine B (2), together with its acetylated analogue, shermilamine B (1), was also strongly cytotoxic against multiple myeloma cell lines. TREM2 is involved in immunomodulatory processes and neurodegenerative diseases. N-deacetylshermilamine B (2) is the first example of a polycyclic alkaloid to show an affinity for this receptor.

Despite the theoretical high productivity, microalgae-based oil production is not economically sustainable due to the high cost of photoautotrophic cultures. Heterotrophic growth is a suitable economic alternative to overcoming light dependence and climatic/geographic fluctuations. Here we report data about growth performance, biomass production, and lipid composition of the marine diatom Cyclotella cryptica, chosen as a model strain for biodiesel production in heterothrophy. A repeated-batch process of heterotrophic cultivation has also been investigated to assess the robustness and phenotypic stability. The process consisting of six constant cycle repetitions was carried out for 42 days and led to an average dry biomass production of 1.5 ± 0.1 g L^-1 of which 20% lipids composed of 60% triglycerides, 20% phospholipids. and 20% glycolipids. The major fatty acids were C16:0 (∼26%), C16:1 ω-7 (∼57%), and C20:5 ω-3 (∼12%), with a significant reduction in the unsaturated fatty acids in comparison to other microalgae grown in heterotrophy. Fatty acids were differently distributed among the glycerolipid classes, and the lipid composition was used to compare the potential properties of C. cryptica oil with traditional vegetable biofuels.