Cognitive function impairment following sleep deprivation (SD) can induce significant aftereffects. Elevated calmodulin (CaM) expression following stroke causes calcium overload-a key contributor to cognitive function impairment. Trifluoperazine (TFP), a CaM inhibitor, reduces CaM overexpression following ischemic stroke. However, it remains unclear whether TFP has influences on cognitive function impairment following SD. We administered TFP to rats subjected to SD. TFP treatment in SD rats reduced cerebral CaM expression and alleviated cognitive function impairment. Improved cognitive function was coincident with increased CaM protein levels and reduced acetyl-CoA synthetase 2 (ACSS2) protein levels after SD. TFP treatment reversed these changes. Our results showed that TFP administration in rats inhibited CaM protein following SD by upregulating ACSS2 protein expression, thereby improving ACSS2-related autophagy and alleviating cognitive function impairment. Consequently, this treatment may promote cerebral cognitive function recovery after SD.

Mast cells contribute to the pathology of various diseases, in particular allergic conditions. Therefore, it is essential to develop strategies that efficiently prevent their harmful effects under such circumstances. Here, we sought to evaluate the possibility of cell death induction as a potential means of selectively depleting mast cells. Previous work has suggested that mast cells are sensitive to regimes that target their acidic secretory granules, and the aim of this study was therefore to identify novel anti-mast cell compounds that act via a granule-mediated pathway. To this end, we evaluated trifluoperazine, an antipsychotic drug known to present lysosomotropic properties. We demonstrate that trifluoperazine is cytotoxic for mast cells, whereas multiple other cell types were resistant. Trifluoperazine induced mainly apoptotic cell death in mast cells. Further, our data indicate that trifluoperazine acts on mast cells by inducing secretory granule permeabilization. In support of this, trifluoperazine caused granule deacidification, accompanied by cytosolic acidification as well as translocation of tryptase from the secretory granules into the cytosol. Trifluoperazine-induced cell death and subsequent DNA degradation were profoundly abrogated when granule acidification was inhibited by the V-ATPase inhibitor bafilomycin A1, suggesting that the granule acidity has a key role in the cell death mechanism. Moreover, mast cell death in response to trifluoperazine was largely caspase-independent, whereas serine protease activity was shown to promote apoptosis-like vs. necrosis-like cell death. Overall, these findings introduce trifluoperazine as a novel anti-mast cell agent that induces cell death through granule permeabilization. Trifluoperazine may thus be evaluated for therapeutic intervention to ameliorate mast cell-mediated detrimental effects.

Cardiovascular disease (CVD) is one of the leading causes of death in patients with severe mental illness (SMI), being ~3.3 times higher than in the general population. The adverse cardiovascular effects of psychiatric medications have short- and long-term consequences that contribute to higher rates of cardiovascular death in patients experiencing SMI. By understanding these adverse effects, clinicians can better address cardiovascular health inequalities in patients with SMI from a pharmacological perspective. This review highlights both the short- and long-term adverse cardiovascular effects of psychiatric medications. These adverse effects include QTc prolongation and torsades de pointes (TdP), which are phenomena associated with certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and antipsychotics. Increasing QT dispersion and induction of Brugada phenotype, both associated with serious cardiac arrhythmias and sudden death, can occur with certain antipsychotics (e.g. trifluoperazine), certain TCAs (e.g. amitriptyline), certain SSRIs (e.g. fluoxetine), methylphenidate and particular mood stabilisers (e.g. lithium). Antipsychotics themselves are associated with increased risk of myocarditis, cardiomyopathy, tachycardia, cardiometabolic derangement, hypertension, orthostatic hypotension and bradycardia. Attention deficit Hyperactivity disorder (ADHD) medications contribute to CVD and tachycardia. Acetylcholinesterase inhibitors (AChEIs) contribute towards bradycardia. Hypertension risk is elevated with serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase A (RIMA) and psychostimulants. Conversely, orthostatic hypotension is associated with certain psychiatric medications, namely TCAs and serotonin antagonist and reuptake inhibitors (SARIs). It is important to note that pharmacokinetic drug-drug interactions, such as inhibition of the cytochrome P450 (CYP450) system, can affect the pharmacodynamic profile of psychiatric medications, thereby increasing the risk of their associated adverse cardiovascular effects. By understanding the main adverse cardiovascular effects of psychiatric medications and prescribing appropriately, clinicians can reduce potential harm in patients with SMI.

Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. Objectives: The present study aimed to develop an efficient synthesis of 8-trifluoromethylquinobenzothiazines and to evaluate the anticancer and antibacterial potential of their N-substituted analogues inspired by triflupromazine, trifluoperazine, and fluphenazine. Methods: 6H-8-Trifluoromethylquinobenzothiazine was synthesized by cyclization of 2-amino-4-trifluoromethylbenzenethiol and 3-bromo-2-chloroquinoline. The resulting quinobenzothiazine, unsubstituted at the nitrogen atom, was subjected to N-alkylation reactions to afford eleven new 6-dialkylaminoalkyl derivatives. Structural elucidation was performed using NMR and HRMS techniques. Anticancer activity was evaluated by MTT assay against human breast (MDA-MB-231), pancreatic (Mia-PaCa-2), and lung (A-549) carcinoma cell lines, as well as normal HaCaT keratinocytes. Antibacterial activity was assessed by MIC/MBC determination against selected Gram-positive and Gram-negative reference strains and clinical isolates. Results: Among the synthesized compounds, derivatives 8 and 12 exhibited the most favorable anticancer profiles, showing micromolar cytotoxicity (IC50 ≈ 4-10 µM) against lung and pancreatic cancer cells combined with moderate selectivity toward cancer cells over normal keratinocytes. Compound 6 displayed lower cytotoxic potency but a notably high selectivity index due to minimal toxicity toward normal cells. In antibacterial assays, compound 3 exhibited activity against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus isolate, with MIC values ranging from 7.8 to 15.6 µg/mL. The corresponding MBC values were equal to or twofold higher than the MICs (MBC/MIC = 1-2), fulfilling commonly accepted criteria for bactericidal activity (MBC/MIC ≤ 4). OD-based growth kinetics confirmed concentration-dependent inhibition of S. aureus growth. Conclusions: The obtained results identify 8-trifluoromethylquinobenzothiazines as a promising class of multifunctional compounds. Selected derivatives combine anticancer activity with acceptable selectivity or display potent antibacterial effects against clinically relevant Gram-positive pathogens.

The ubiquitin-proteasome system (UPS) is a crucial determinant of protein stability and activity in various aspects of physiological function and disease development. The well-characterized class of regulatory enzymes within the UPS is deubiquitinating enzymes (DUBs), and their effects, particularly those of the ubiquitin-specific proteases (USPs), oppose ubiquitination. All DUB activities can be more or less disrupted in various cancers, including breast cancer, and DUB alterations contribute substantially to tumor initiation, progression, and many forms of therapeutic resistance. In this review, we discuss the various molecular mechanisms of action of USPs on breast cancer hallmarks, including proliferation, aggression or metastasis, evasion of apoptosis, immune evasion, and metabolic programming. We evaluate how specific USPs stabilize oncogene members by deubiquitinating target proteins or deubiquitinating tumor suppressors, thereby influencing a variety of cellular behaviors, from regulating the cell cycle to modulating immune responses. Due to their important role in breast cancer pathology, the alterations of USP activities and the functional roles of selective USPs will also demonstrate some ways USPs present promising therapeutic targets in breast cancer. We will provide a comprehensive overview of USP inhibitors to date, focusing on their utilization in developing and describing efficacy in breast cancer models. Pharmacological inhibitors of specific USPs, such as pimozide, trifluoperazine, rottlerin, 6-thioguanine, and costunolide, are highlighted for their potential to inhibit proliferation, metastasis, induce apoptosis, and circumvent therapy resistance across breast cancer subtypes (triple-negative and HER-2 positive). The review highlights the complex and often contradictory roles of USPs in breast cancer and points to the immense promise of targeting these enzymes to develop new and efficacious anticancer therapies.

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening reaction to antipsychotic medication. This report describes the case of a 62-year-old male with chronic trifluoperazine use who presented with fever, rigidity, and altered mental status. Although sepsis or meningoencephalitis was initially suspected, an elevated creatine kinase and fulfillment of Levenson's criteria confirmed the diagnosis of NMS. The patient's condition improved following supportive care, administration of bromocriptine, and lorazepam. This case highlights the diagnostic challenges of NMS in patients on a stable antipsychotic regimen and underscores the importance of early recognition, particularly after excluding infectious etiologies.

With millions of cases reported annually, fungal infections represent a growing public health concern. The effectiveness of current treatment options is hindered by the availability of only three antifungal drug classes, rising resistance, and suboptimal efficacy against certain pathogens. One promising strategy to overcome these challenges is to enhance the antifungal activity of existing drugs while maintaining favorable pharmacokinetic profiles. Herein, we describe the repurposing and optimization of a series of phenoxazine analogs of the antipsychotic drugs fluphenazine and trifluoperazine as antifungals. Optimization and the structure activity relationship studies identified novel phenoxazine derivatives as potent antifungal agents against Cryptococcus neoformans and Candida albicans (MIC 1-4 μg/mL and 2-8 μg/mL, respectively, 4-16 fold more potent than fluphenazine and trifluoperazine). In addition, the POZ analogs displayed reduced affinities towards serotonin and dopamine receptors compared to trifluoperazine. However, potent and moderately selective POZ analog 61 failed to demonstrate efficacy in a mouse model of cryptococcosis, demonstrating the need for further optimization.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management.

Phospholipases are major regulators of lipid-dependent signaling and play crucial roles in plant immunity. Rice (Oryza sativa) phospholipase C4 (OsPLC4) is a major functional enzyme in the rice phospholipase family that regulates intracellular Ca[2+] levels. Here we show that OsPLC4 translocates primarily to the plasma membrane in a Ca[2+]-dependent manner, with its C2 domain functioning as a membrane trafficker. Transient expression of OsPLC4 and its truncated variants triggers cell death and immune responses in plants. During effector-triggered immunity (ETI) in rice, OsPLC4 expression and Ca[2+] influx are specifically and strongly induced in response to avirulent Magnaporthe oryzae. Upon infection, the rice Osplc4 knockout mutant (ΔOsplc4) exhibits substantially reduced Ca[2+], reactive oxygen species (ROS), and Fe[3+] accumulation, as well as diminished lipid peroxidation and hypersensitive response (HR) cell death. Complementation of ΔOsplc4 can fully restore Ca[2+]-mediated ferroptotic cell death. OsPLC4 expression also activates HR cell death and the expression of defense-related genes such as OsRbohB, OsMEK2, OsMPK1, and OsPAL1 during avirulent M. oryzae infection. The Ca[2+] chelator ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) substantially inhibits Ca[2+], ROS, and Fe[3+] accumulation and HR-related cell death in rice, whereas the Ca[2+] influx enhancers trifluoperazine hydrochloride (TFP) and acibenzolar-S-methyl (ASM) strongly induce Ca[2+]-mediated ferroptotic cell death. Additionally, OsPLC4 overexpression triggers cell death and immune responses in Arabidopsis. Collectively, our findings demonstrate that OsPLC4 acts as a downstream target of resistosome activation and sustains the co-elevation of Ca[2+] and ROS levels during rice ETI, thereby promoting Ca[2+]-mediated, lipid ROS-dependent ferroptotic cell death. These results establish OsPLC4 as a key regulator of Ca[2+]-dependent plant immunity.

Trifluoperazine (TFP), an antipsychotic used in depression management, suffers from extensive first-pass metabolism and poor oral bioavailability. Intranasal delivery offers a promising non-invasive route for direct nose-to-brain targeting, while magnetic nanoparticles can further enhance drug localization and absorption. This study aimed to optimize and evaluate a superparamagnetic iron oxide nanoparticle (SPION)-loaded leciplex organogel for intranasal delivery of TFP, with emphasis on the effect of external magnet location. The study compared magnet application on the brain to promote olfactory targeting versus on the nose to enhance systemic absorption. TFP/SPION-leciplex nanoparticles were optimized and incorporated into a thermosensitive mucoadhesive organogel. Pharmacodynamic efficacy was assessed via the forced swimming test, and pharmacokinetics were determined in plasma and brain across four groups: no magnet, magnet on nose, magnet on brain, and oral marketed product. The optimized formulation (266.20 nm, +50.9 mV, 5.90 emu/g, IC50 393.92 μg/ml) showed safety and favorable characteristics. Both magnet-assisted groups significantly reduced immobility time versus the non-magnet and oral controls, with no significant difference between the two strategies. However, the "magnet on nose" group achieved the highest plasma levels, favoring systemic absorption, while the "magnet on brain" group achieved the highest brain levels, favoring olfactory targeting. The SPION-loaded leciplex organogel significantly improved intranasal TFP delivery, enabling dose reduction and superior efficacy compared with oral therapy. Magnet placement was profound in directing drug distribution toward systemic circulation or brain, suggesting that the two approaches may be clinically tailored-"magnet on nose" for systemic delivery and "magnet on brain" for CNS targeting.

Squalene epoxidase (SQLE) is a crucial enzyme in the cholesterol-biosynthesis pathway and a promising target for treating cholesterol-related disorders. This study aimed to repurpose eighteen clinically approved phenothiazine antipsychotics as competitive SQLE inhibitors by integrating structure-based virtual screening, 200 ns molecular-dynamics simulations, MM/PBSA binding-energy calculations and in vitro enzyme assays. We first screened the 18 derivatives using molecular docking, structural/pharmacological diversity and ADMET analysis. Six compounds-ethopropazine, periciazine, piperacetazine, dixyrazine, fluphenazine and trifluoperazine-were prioritized for detailed MD simulations and MM/PBSA evaluation. Potential-energy-landscape analysis revealed that ethopropazine, periciazine and piperacetazine formed the most stable enzyme-ligand complexes, each occupying well-defined energy wells. Corresponding ΔGtotal values of - 27.05 ± 2.10 kcal mol⁻¹, - 27.84 ± 1.67 kcal mol⁻¹ and - 26.94 ± 1.82 kcal mol⁻¹ indicated high binding affinities. In vitro assays confirmed potent SQLE inhibition, with IC₅₀ values of 1.69 ± 0.06 µM, 1.55 ± 0.13 µM and 1.44 ± 0.04 µM, respectively; kinetic studies established competitive inhibition with Ki values of 0.65-0.69 µM. The strong correlation between computational predictions and experimental data underscores the effectiveness of our integrated approach and identifies ethopropazine, periciazine and piperacetazine as promising lead compounds for further optimization and pre-clinical development as SQLE inhibitors.

This study aims to examine the changes in AQP4 polarity and pericyte vascularity during temporal lobe epilepsy (TLE) progression, with the goal of identifying potential drug targets or strategies to delay the onset and progression of TLE. Chronic TLE was induced in male rats using pilocarpine. AQP4 polarity and pericyte vascular coverage were assessed by immunofluorescence. The effects of modulating AQP4 polarity on PTZ-induced TLE model using male mice were studied. Molecular mechanisms of AQP4 polarity were explored using transwell coculture and transcriptomics, validated at the protein level. ELISA was used to measure PDGF-BB levels in serum and cerebrospinal fluid. Following pilocarpine-induced chronic TLE model establishment, AQP4 polarity and pericyte vascular coverage rapidly increased but later declined, reaching the lowest levels in epileptic animals. Trifluoperazine prevented AQP4 redistribution, reduced seizure duration, and alleviated brain edema in PTZ-induced TLE mouse model. Transcriptomic analysis revealed that pericyte coculture did not alter the expression of dystrophin-associated protein components in astrocytes. Pericyte LAMA1 and LAMA2 levels were significantly higher than endothelial cells, and the levels of pericyte LAMA1 and LAMA2 were significantly increased after coculture with astrocytes. Expression of LAMA1 and LAMA2 around pericytes initially increased and then decreased during chronic TLE progression. PDGF-BB levels decreased over time, reaching the lowest levels during epilepsy. Disrupted AQP4 polarity is closely associated with TLE development. Pericyte vascular coverage appears to influence AQP4 polarity, and key molecules such as laminins and PDGF-BB may help maintain AQP4 polarity, potentially contributing to the attenuation of TLE progression and epileptogenesis.