Omar Lozano

Cardiorenal syndrome (CRS) is characterized by bidirectional heart–kidney dysfunction in which oxidative stress, inflammation, and mitochondrial dysfunction drive progressive kidney injury, but the role of mitochondrial calcium (Ca²⁺) handling through the mitochondrial calcium uniporter (MCU) complex remains unclear. Here we show, in a mouse model of CRS induced by angiotensin II and L-NAME in male mice (C57BL/6), that renal mitochondria exhibit increased MCU expression, reduced Ca²⁺ retention capacity, and greater susceptibility to Ca²⁺-induced permeability transition, alongside impaired respiration, reduced PGC-1α and TFAM expression, oxidative stress, and inflammatory activation. Cannabidiol (CBD) attenuates renal dysfunction and structural injury, restores mitochondrial respiratory capacity and complex I activity, normalizes MCU expression, and partially improves mitochondrial Ca²⁺ handling, independently of blood pressure reduction. These findings identify MCU-dependent mitochondrial Ca²⁺ dysregulation as a candidate mechanism linking mitochondrial dysfunction to renal injury in CRS, and a potential target for CBD’s nephroprotective effects.

The role of saturated fatty acid-induced immunometabolic stress in macrophage dysfunction during metabolic disease remains incompletely understood, particularly the interplay between inflammatory signaling and intracellular lipid handling. We employed a tightly controlled palmitic acid (PA)-based lipotoxicity model in PMA-differentiated U937-derived human macrophage-like cells to investigate how lipid excess reshapes inflammatory responses and to evaluate the modulatory effects of cannabidiol (CBD). PA exposure induced a metabolically stressed yet viable macrophage phenotype, characterized by a broad cytokine remodeling profile. This included induction of classical proinflammatory cytokines such as interleukin (IL)-6, together with activation of inflammasome-associated cytokines IL-1β and IL-18 and additional immunoregulatory mediators, while tumor necrosis factor alpha (TNF-α) contributed to the overall inflammatory profile in a multivariate analysis. These changes were accompanied by a significant, time-dependent storage of intracellular triglycerides (TG) consistent with lipid overload and altered lipid handling. CBD co-treatment did not compromise cell viability but selectively attenuated PA-induced inflammatory response in a cytokine-dependent manner, with the most significant reduction observed at higher concentrations. In parallel, CBD significantly reduced intracellular TG accumulation under lipotoxic conditions. Collectively, these findings define a lipotoxicity-associated macrophage phenotype driven by saturated fatty acids and identify CBD as a context-dependent modulator of immunometabolic inflammation. This work provides a controlled experimental framework to study lipid-driven inflammatory dysfunction and supports the potential of CBD as a targeted strategy to modulate metabolic inflammation without broadly suppressing immune function.

The intricate interplay between macrophage biology and lipid metabolism has emerged as a critical determinant of metabolic homeostasis, disease progression and pathogenesis. This comprehensive review explores the molecular mechanisms through which fatty acids activate macrophage function, emphasizing their selective engagement of pattern recognition receptors such as Toll-like receptors (TLRs), CD36, and GPR120. Notably, saturated fatty acids (SFAs) like lauric acid (C12:0) and palmitic acid (C16:0) activate TLR2 and TLR4 signaling pathways. Palmitic acid triggers mitochondrial dysfunction and lysosomal destabilization, leading to NLRP3 inflammasome activation and chronic low-grade inflammation. In contrast, ω-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid, help resolve inflammation through GPR120-mediated signaling and the production of specialized pro-resolving mediators (SPMs) like resolvins, protectins, and maresins. This review establishes a paradigm for understanding the complex relationship between dietary lipids, innate immunity, and metabolic health, with broad implications for immunometabolic interventions.

In this study, membranes of collagen–chitosan (C-Ch) in combination with conductive polymers (CPs) such as polyaniline (Pani) and polypyrrole (Ppy) were obtained by electrospinning using non-toxic solvents such as PBS and ethanol. The change in the morphology after swelling was observed by SEM, while an FTIR analysis showed specific interactions between C-Ch and CP. Mechanical tests showed that C-Ch/Ppy exhibited more elastic behavior and a better stress distribution compared to C-Ch/Pani. The diffusion of Na⁺ and Ca²⁺ ions through the membranes was evaluated and showed a greater resistance for Ca²⁺ in both membrane types. Preliminary biocompatibility testing with H9C2 cells showed a successful cell adhesion to the membranes. These results emphasize the potential of C-Ch/Pani composites for electrically active scaffolds and of C-Ch/PPy composites for applications in mechanically dynamic tissue-specific regeneration.

Background and Aim: Over the past years, noble metal-based nanoparticles have been extensively investigated for their applications in nanomedicine. However, there are still concerns about the potential adversities that these nanoparticles may present in an organism. In particular, whether they could cause an exacerbated cytotoxic response in susceptible tissues due to damage or disease, such as the heart, liver, spleen, or kidneys. In this regard, this study aims to evaluate the cytotoxicity of mono- and bimetallic nanoparticles of gold and silver (Au:Ag NPs) on healthy and hypertrophic cardiac H9c2 cells, and on healthy and metabolically activated macrophages derived from U937 cells. The main objective of this work is to explore the susceptibility of cells due to exposure to Au:Ag NPs in conditions representing cardiometabolic diseases. Methods: Au:Ag NPs were synthesized in different molar ratios (Au:Ag, 100:0, 75:25, 50:50, 25:75, 0:100) using starch as a capping and reducing agent. Their physicochemical properties were characterized through UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), ζ-potential measurements, and transmission electron microscopy (TEM). Moreover, the effect of the metal-based nanoparticle exposure on healthy and hypertrophic H9c2 cells was measured by analyzing the cellular vitality, the loss of mitochondrial membrane potential (∆Ψm), and the production of mitochondrial reactive oxygen species (mROS). Results: The Au:Ag NPs did not affect the cell vitality of healthy or metabolically activated macrophages. On the contrary, healthy H9c2 cells showed decreased mitochondrial metabolism when exposed to NPs with higher Ag concentrations. Furthermore, hypertrophic H9c2 cells were more susceptible to the same NPs compared to their non-hypertrophic counterparts, and presented a pronounced loss of ∆Ψm. In addition, these NPs increased the production of mROS and regulated cell death in both cardiac cells. Conclusion: In conclusion, low doses of high-Ag load in Au:Ag NPs produced cytotoxicity on H9c2 cardiac cells, with hypertrophic cells being more susceptible. These results suggest that cardiac hypertrophic conditions are more prone to a cytotoxic response in the presence of bimetallic Au:Ag NPs compared to healthy cells. In addition, this work opens the door to explore the nanotoxicity of noble metal-based NPs in biological disease conditions.