Mitocurcumin (a triphenylphosphonium curcumin derivative) was previously reported as a selective antitumoral compound on different cellular lines, as well as a potent bactericidal candidate. In this study, the same compound showed strong antimicrobial efficacy against different strains of methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration was identical for all tested strains (four strains of MRSA and one strain of methicillin-sensitive Staphylococcus aureus), suggesting a new mechanism of action compared with usual antibacterial agents. All tested strains showed a significant sensitivity in the low micromolar range for the curcumin-triphenylphosphonium derivative. This susceptibility was modulated by the menadione/glutathione addition (the addition of glutathione resulted in a significant increase in minimal inhibitory concentration from 1.95 to 3.9 uM, whereas adding menadione resulted in a decrease of 0.49 uM). The fluorescence microscopy showed a better intrabacterial accumulation for the new curcumin-triphenylphosphonium derivative compared with simple curcumin. The MitoTracker staining showed an accumulation of reactive oxygen species (ROS) for a S. pombe superoxide dismutase deleted model. All results suggest a new mechanism of action which is not influenced by the acquired resistance of MRSA. The most plausible mechanism is reactive oxygen species (ROS) overproduction after a massive intracellular accumulation of the curcumin-triphenylphosphonium derivative.

The limited antifungal drugs available and the rise of multidrug-resistant Candida species have made the efforts to improve antifungal therapies paramount. To this end, our research focused on the effect of a combined treatment between chemical and photodynamic therapy (PDT) towards a fluconazole-resistant clinical Candida albicans strain. The co-treatment of PDT and curcumin in various doses with fluconazole (FLC) had an inhibitory effect on the growth of the FLC-resistant hospital strain of C. albicans in both difusimetric and broth microdilution methods. The proliferation of the cells was inhibited in the presence of curcumin at 3.125 µM and FLC at 41 µM concentrations. The possible involvement of oxidative stress was analyzed by adding menadione and glutathione as a prooxidant and antioxidant, respectively. In addition, we examined the photoactivated curcumin effect on efflux pumps, a mechanism often linked to drug resistance. Nile Red accumulation assays were used to evaluate efflux pumps activity through fluorescence microscopy and spectrofluorometry. The results showed that photoactivated curcumin at 3.125 µM inhibited the transport of the fluorescent substrate that cells usually expel, indicating its potential in combating drug resistance. Overall, the findings suggest that curcumin, particularly when combined with PDT, can effectively inhibit the growth of FLC-resistant C. albicans, addressing the challenge of yeast resistance to azole antifungals through upregulating multidrug transporters.

Background/Objectives: Epilepsy is a complex neurological disorder with a strong link to oxidative stress, which contributes to seizure susceptibility and neuronal damage. This study aims to investigate the effects of curcumin (Cur), sodium valproate (VPA), and mitocurcumin (MitoCur), a mitochondria-targeted curcumin, on behavioral and oxidative stress parameters in a zebrafish model of pentylenetetrazole (PTZ)-induced seizures. Methods: Adult zebrafish were exposed to two concentrations (0.25 and 0.5 µM for Cur and MitoCur; 0.25 and 0.5 mM for VPA). Behavioral assessments, including locomotion, spatial exploration, and directional movement, were conducted using EthoVision XT tracking software. Oxidative stress markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx), and total antioxidant status (TAS), were analyzed in brain homogenates. Results: Behavioral analyses indicated dose-dependent effects, with higher doses generally reducing activity. MitoCur at 0.25 µM enhanced antioxidant defenses and reduced oxidative damage, while higher doses exhibited a pro-oxidant shift. VPA at 0.25 mM improved TAS without significantly altering MDA levels. Conclusions: These findings emphasize the importance of dose optimization in antioxidant-based epilepsy treatments and highlight the potential of MitoCur as a targeted therapeutic option.

Background/Objectives: Ongoing challenges in epilepsy therapy warrant research on alternative treatments that offer improved efficacy and reduced side effects. Designed to enhance mitochondrial targeting and increase bioavailability, mitocurcumin (MitoCur) was evaluated for the first time as an antiepileptic agent, with curcumin (Cur) and sodium valproate (VPA), a standard antiepileptic drug, included for comparison. This study investigated the effects on seizure onset, severity, and progression in a zebrafish model of pentylenetetrazole (PTZ)-induced seizures and measured the concentrations of the compounds in brain tissue. Methods: Zebrafish were pre-treated with MitoCur and Cur (both at 0.25 and 0.5 µM doses) and VPA (0.25 and 0.5 mM) and observed for four minutes to establish baseline locomotor behavior. Subsequently, the animals were exposed to a 5 mM PTZ solution for 10 min, during which seizure progression was observed and scored as follows: 1—increased swimming; 2—burst swimming, left and right movements; 3—circular movements; 4—clonic seizure-like behavior; 5—loss of body posture. The studied compounds were quantified in brain tissue through HPLC and LC-MS. Results: Compared to the control group, all treatments reduced the distance moved and the average velocity, without significant differences between compounds or doses. During PTZ exposure, seizure latencies revealed that all treatments effectively delayed seizure onset up to score 4, demonstrating efficacy in managing moderate seizure activity. Notably, MitoCur also provided significant protection against the most severe seizure score (score 5). Brain tissue uptake analysis indicated that MitoCur achieved higher concentrations in the brain compared to Cur, at both doses. Conclusions: These results highlight the potential of MitoCur as a candidate for seizure management.

Ocular pharmacotherapy is constrained by compartmental anatomy and clearance barriers that limit sustained posterior-segment exposure. Intravitreal bolus

Background/Objectives: Manganese–Curcumin–Triphenylphosphonium (Mn-C-TPP), a complex designed for mitochondrial targeting, was investigated with ascorbate to assess cytotoxicity and associated cellular responses. We hypothesized that Mn-C-TPP would amplify ascorbate-driven oxidative stress and produce synergistic cytotoxicity in susceptible cancer cell lines. Methods: An inverse, control-normalized SYTOX-derived response index (vehicle = 100; staurosporine = 0) was determined after 72 h in HCT116, A549, HepG2, and normal dermal human fibroblasts (NDHFs). H₂O₂-associated luminescence (ROS-Glo), caspase-3/7 activation, and mitochondrial membrane potential were assessed in selected cancer cell lines. Drug interactions were analyzed using SynergyFinder 3.0 (ZIP model). Results: Mn-C-TPP alone reduced the SYTOX-derived response index in HCT116 and HepG2, whereas A549 and NDHF showed smaller changes. Ascorbate enhanced cytotoxicity at selected combinations. In HCT116, 3 µM Mn-C-TPP plus 100 µM ascorbate decreased the SYTOX-derived response index toward the staurosporine reference. HepG2 responded markedly to 3–7 µM Mn-C-TPP with 100–300 µM ascorbate, whereas pronounced A549 responses occurred mainly at 15–30 µM Mn-C-TPP with 100–300 µM ascorbate. Mean ZIP scores were approximately 32, 54, 6, and 10 for HCT116, HepG2, A549, and NDHF, respectively. The NDHF response index remained close to the vehicle reference at lower combination doses but decreased at higher doses. Cellular assays showed increased H₂O₂-associated luminescence with Mn-C-TPP alone and higher mean signals with selected combinations than with ascorbate alone, together with caspase-3/7 activation and mitochondrial depolarization. Conclusions: These findings demonstrate cell-line- and concentration-dependent cytotoxicity and support further investigation of the proposed mitochondrial redox mechanism.