Active inference is a leading theory in neuroscience that provides a simple and neuro-biologically plausible account of how action and perception are coupled in producing (Bayes) optimal behavior; and has been recently used to explain a variety of psychopathological conditions. In parallel, morphogenesis has been described as the behavior of a (non-neural) cellular collective intelligence solving problems in anatomical morphospace. In this article, we establish a link between the domains of cell biology and neuroscience, by analyzing disorders of morphogenesis as disorders of (active) inference. The aim of this article is three-fold. We want to: (i) reveal a connection between disorders of morphogenesis and disorders of active inference as apparent in psychopathological conditions; (ii) show how disorders of morphogenesis can be simulated using active inference; (iii) suggest that active inference can shed light on developmental defects or aberrant morphogenetic processes, seen as disorders of information processing, and perhaps suggesting novel intervention and repair strategies. We present four simulations illustrating application of these ideas to cellular behavior during morphogenesis. Three of the simulations show that the same forms of aberrant active inference (e.g., deficits of sensory attenuation and low sensory precision) that have been used to explain psychopathological conditions (e.g., schizophrenia and autism) also produce familiar disorders of development and morphogenesis when implemented at the level of the collective behavior of a group of cells. The fourth simulation involves two cells with too high precision, in which we show that the reduction of concentration signaling and sensitivity to the signals of other cells treats the development defect. Finally, we present the results of an experimental test of one of the model's predictions in early Xenopus laevis embryos: thioridazine (a dopamine antagonist that may reduce sensory precision in biological systems) induced developmental (anatomical) defects as predicted. The use of conceptual and empirical tools from neuroscience to understand the morphogenetic behavior of pre-neural agents offers the possibility of new approaches in regenerative medicine and evolutionary developmental biology.

Because there is no published experience with thioridazine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Psychiatric drugs released by humans in wastewater have received more attention because of their potential risks for aquatic organisms. In this study, the occurrence of the two most common groups of psychiatric drugs (sedatives-hypnotics-anxiolytics and antidepressants) were evaluated in the Tehran South Municipal Wastewater Treatment Plant. All the target sedatives-hypnotics-anxiolytics (alprazolam, phenobarbital, and thioridazine) and antidepressants (fluoxetine, citalopram, sertraline, and venlafaxine) were observed in influent and secondary clarification (SC) effluent. Thioridazine (164.25 ± 218.74 ng/L) and citalopram (672.53 ± 938.56 ng/L) had the highest mean concentrations in the influent, while alprazolam (5.09 ± 2.33 ng/L) and citalopram (776.97 ± 1088.01 ng/L) had the highest concentrations in the SC effluent. The higher concentrations of the psychiatric drugs, except thioridazine, were detected in the SC effluent compared to the concentrations in the influent. The increased drugs concentrations, with negative removal efficiencies, were more distinctive in the cold season samples. Psychiatric drugs processed in the chlorination unit followed a completely different pattern compared to the drugs in the biological treatment unit. All the drugs' concentrations, except thioridazine, decreased in the chlorination unit, ranging between 27 ± 14% for alprazolam and 75 ± 10% for citalopram. However, the mean concentrations of the detected drugs were as follows: sertraline (11.96 ± 11.62 ng/L) and venlafaxine (184.94 ± 219.74 ng/L) which could cause environmental and ecological concerns.

Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

It is important for clinicians to consider exposure to toxic substances and nutritional deficiencies when diagnosing and managing cases of vision loss. In these cases, physiologic damage can alter the function of key components of the visual pathway before morphologic changes can be detected by traditional imaging methods. Electrophysiologic tests can aid in the early detection of such functional changes to visual pathway components, including the retina or optic nerve. This review provides an overview of various electrophysiologic techniques, including multifocal electroretinogram (mfERG), full-field ERG (ffERG), electrooculogram (EOG), pattern electroretinogram (PERG), and visual evoked potential (VEP) in monitoring the retinal and optic nerve toxicities of alcohol, amiodarone, cefuroxime, cisplatin, deferoxamine, digoxin, ethambutol, hydroxychloroquine, isotretinoin, ocular siderosis, pentosane, PDE5 inhibitors, phenothiazines (chlorpromazine and thioridazine), quinine, tamoxifen, topiramate, vigabatrin, and vitamin A deficiency.

Psychiatric disorders are a heterogeneous group of mental disorders that manifest as abnormal mental or behavioral habits that cause the individual discomfort or disability. Dopamine imbalance plays a major role in many psychiatric disorders. Piperine, Curcumin and Capsaicin are CYP P450 3A4 & 2D6 inhibitors. The objective of this study is to determine the dopaminergic activity of Piperine, Curcumin and Capsaicin and also to compare cytochrome P450 3A4 and 2D6 inhibition activity by in-silico methods. In this in-silico study, we utilised compounds such as Piperine, Curcumin and Capsaicin were subjected to Lipinski's rule of five, and ligands were also evaluated for toxicity profile and ADMET properties. Furthermore, the ligands were performed in docking studies. All three compounds were docked with three different targeted proteins (PDB IDs: 4D7D, 4WNW and 6LUQ). According to the docking result, Piperine has higher binding energy(-8.55 kcal/mol)(-8.1 kcal/mol)(-8.57 kcal/mol) when compared with Curcumin(-7.39 kcal/mol)(-5.61 kcal/mol)(-6.57 kcal/mol) and Capsaicin (-6.86 kcal/mol)(-6.57 kcal/mol)(-5.42 kcal/mol) and also with standard drug (-8.61 kcal/mol)(-7.65 kcal/mol)(-6.16 kcal/mol). The present study concluded that the bioactive compound Piperine has a better inhibitory activity of CYP 3A4, 2D6 enzymes and dopamine D2 receptor among the three compounds and also with the standard drug thioridazine.

Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are closely related to tumorigenesis and metastasis. Thioridazine (THZ) is a usual phenothiazine antipsychotic drug that can destroy CSCs. We aimed to explore whether THZ could sensitize metastatic TNBC cells, especially the CSCs, to carboplatin (CBP) treatment. Metastatic TNBC cells, 4T1 cells, and tumor-bearing mice were treated with THZ and CBP as monotherapy or combination therapy. MTT, flow cytometry, electron microscopy, immunohistochemistry and western blotting were applied to assess the cell viability, apoptosis, mitochondrial morphology and the relevant protein levels, respectively. Tumor size and lung metastasis under different treatments as well as tumorigenesis of residual tumor cells from each group were monitored. THZ combined with CBP inhibited 4T1 tumor cell proliferation and induced apoptosis by inhibiting the PI3K-AKT-mTOR pathway and activating estrogen receptor stress. THZ also showed strong activity against breast CSCs, THZ combined with CBP significantly destroyed cancer cells, inhibited lung metastasis and relieved the tumor burden; Our data demonstrated that THZ can sensitize TNBC cells to CBP treatment and this combination therapy may provide a bright strategy for TNBC treatment by targeting both cancer cells and CSCs.

In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.

Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA beta-oxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administration‒approved drug ranolazine carries translational potential.

Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival.[1] Countless studies have been published supporting Dr. Gideon Koren's 1993 landmark article "Medications Which Can Kill a Toddler with One Tablet or Teaspoonful" in the Journal of Toxicology.[2][3][4][5] while each has its own merits, most focus solely on pediatric overdoses, and relatively few of them provide an exhaustive list or act as a "quick-reference" when dealing with real-time ingestions.  Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur.  In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age.  Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications.  Adult overdoses usually are due to the intentional ingestion of analgesics and sedative-hypnotics.  Following are the list of toxic drugs (in decreasing severity/difficulty of treatment) included in this summary:  1. Alpha-2 adrenergic agonists - clonidine, naphazoline, oxymetazoline, tetrahydrozoline. 2. Sulfonylureas - chlorpropamide, glyburide, glipizide, glimepiride. 3. Calcium channel blockers - nifedipine, verapamil, diltiazem, amlodipine, nicardipine. 4. Beta-blockers - metoprolol, labetalol. 5. Tricyclic antidepressants - imipramine, desipramine, amitriptyline, nortriptyline. 6. Opioids - codeine, hydrocodone, methadone, morphine, heroin. 7. Anti-diarrheals - diphenoxylate + atropine, loperamide. 8. Salicylates/Methyl salicylates - wintergreen oil, bismuth subsalicylate, mentholated balms. 9. Antipsychotics - loxapine, thioridazine, chlorpromazine. 10. Antimalarials - chloroquine, hydroxychloroquine, quinine. 11. Antiarrhythmics - quinidine, disopyramide, procainamide, flecainide. 12. Terpenoid (camphor) - analgesic, anti-itch, and cooling gels, ointments, and balms. 13. Non-alkaloid toxic lignan - podophyllin, podofilox. 14. Plant toxin/secondary metabolite - colchicine. 15. Oral acetylcholinesterase inhibitors - rivastigmine, donepezil, galantamine. 16. Methylxanthine - theophylline: 1,3-dimethylxanthine. 17. Partial opioid agonist/synthetics - buprenorphine/fentanyl. 18. Toxic alcohols - methanol, ethylene glycol. 19. Caustics /household products - acidic or alkaline household products, hydrofluoric acid, selenious acid, ammonia fluoride, methacrylic acid (cosmetic glue), naphthalene (mothballs).

Risky decision-making is the decision made by individuals when they know the probability of each outcome. In order to survive in unpredictable environments, it is necessary for individuals to assess the probability of events occurring to an make appropriate decisions. There are few studies on the neural basis of risky decision-making behavior guided by external cues, which is related to the relative paucity of animal behavioral paradigms. Previous studies have shown that the prefrontal cortex (PFC) plays a key role in risk-based decision-making. The PFC receives projections from the dopamine (DA) system from the ventral tegmental area of the midbrain. The mesocorticolimbic DA system regulates the judgments of reward and value in decision-making. However, the specific receptor mechanism for prefrontal DA regulation of cue-guided risky decision-making behavior remains unclear. Here we established a cue-guided risky decision-making behavioral paradigm (RDM task) to detect the behavior of rats making decisions between a small certain reward and a large uncertain reward in a self-paced manner. The D1 receptor antagonist SCH-23390 (5 mM) or agonist SKF-82958 (5 mM), and the D2 receptor antagonist thioridazine hydrochloride (5 mM) or agonist MLS-1547 (5 mM) was injected into the mPFC, respectively, to investigate how the behavior in the RDM task was changed. The results showed that: (1) rats were able to master the operation of the cue-guided RDM task in a self-paced way; (2) a majority of rats were inclined to choose risk rather than a safe option when the reward expectations were equal; and (3) risk selection was reduced upon inhibition of D1 receptors or stimulation of D2 receptors, but increased upon stimulation of D1 receptors or inhibition of D2 receptors, suggesting that the RDM performance is regulated by D1 and D2 receptors in the mPFC. The present results suggest that DA receptors in the mPFC of rats are involved in regulating cue-guided RDM behavior, with differential involvement of D1 and D2 receptors in the regulation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, generating new variants that pose a threat to global health; therefore, it is imperative to obtain safe and broad-spectrum antivirals against SARS-CoV-2 and its variants. To this end, we screened compounds for their ability to inhibit viral entry, which is a critical step in virus infection. Twenty compounds that have been previously reported to inhibit SARS-CoV-2 replication were tested by using pseudoviruses containing the spike protein from the original strain (SARS-CoV-2-WH01). The cytotoxicity of these compounds was determined. Furthermore, we identified six compounds with strong antagonistic activity against the WH01 pseudovirus, and low cytotoxicity was identified. These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2 (Delta) and B.1.1.529 (Omicron), the two most prevalent circulating strains. These assays demonstrated that two phenothiazine compounds, trifluoperazine 2HCl and thioridazine HCl, inhibit the infection of Delta and Omicron pseudoviruses. Finally, we discovered that these two compounds were highly effective against authentic SARS-CoV-2 viruses, including the WH01, Delta, and Omicron strains. Our study identified potential broad-spectrum SARS-CoV-2 inhibitors and provided insights into the development of novel therapeutics.

In this study, the corrosion inhibition efficiency of thioridazine hydrochloride (TH), an antipsychotic drug, on mild steel (commonly used pipeline material in the oil and gas industry) in 1 M hydrochloric acid (HCl) was evaluated using electrochemical techniques and weight loss method. Electrochemical impedance spectroscopy (EIS) results suggest that TH significantly enhances the polarization resistance (Rp) of mild steel. Similarly, potentiodynamic polarization results showed that the corrosion current density (icorr) of mild steel decreased significantly with addition of TH. To understand the long-term effect of TH, mild steel was tested for 7 days in 100 ppm TH containing electrolyte. EIS results showed that the Rp did not change significantly after 24 h exposure as compared to 2 h exposure; whereas the Rp increased by 28% after 7-day exposure. Weight loss measurements revealed that the inhibition efficiency of TH is remarkably high (98.8%) after 7-day exposure. The adsorption free energy calculation suggests that at the initial stage (1-day) of mild steel exposure, TH was physically adsorbed onto the surface. However, at a later stage (7- day) the binding of TH was chemical, and hence the corrosion protection increased with increase in the exposure period. As compared to the wide range of corrosion inhibitors reported in the literature, TH has shown to be highly effective for mild steel. Thus, it can be suggested that TH drug waste is a potential corrosion inhibitor for mild steel pipelines in the oil and gas industry.

Similar to other first-generation or typical antipsychotics, thioridazine is a medication used to treat schizophrenia. Other indications for use include other psychotic disorders, depressive disorders, pediatric behavioral disorders, and geriatric psychoneurotic manifestations. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, toxicity, and monitoring, of thioridazine, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Thioridazine was used to sensitize cisplatin against cisplatin-resistant human lung cancer cells. Cells received thioridazine, cisplatin, or both drugs (the combination). Thioridazine synergized cisplatin to increase percentages of dead and apoptotic cells. DNA damage was detected using the comet assays; the combination led to the highest alkaline- and neutral-comet percentages, demonstrating exacerbation of both single- and double-strand breaks. After thioridazine treatment, levels of glutathione, and BRCA2, RAD51, and ERCC1 proteins were decreased. These data manifested that thioridazine decreased the capacities of detoxification and DNA repair, thereby enhancing cisplatin-induced DNA damage in resistant cells.

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC50) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC50 value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou-Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs.

Pending updates to ICH S7B/E14 guidelines will enable the substitution of human TQT studies with support from concomitant negative hERG and non-rodent CV studies. This retrospective analysis compared the effects of thioridazine (THD) (5-20 mg/kg) on heart rate (HR), blood pressure (BP), body temperature (Tc), and QT in the dog (n = 6), cynomolgus monkey (n = 4), and Goettingen minipig (n = 4) with data from previously completed studies employing crossover designs. As QT measurements are confounded by HR and Tc changes, QT effects were individually corrected for changes in HR (QTca) and Tc (QTcaT). THD-induced hemodynamic changes seen in humans were most accurately reflected in the monkey and, to a lesser extent, the dog, but not in the minipig. The minipig was most sensitive to THD QTc effects. When QTca was adjusted for THD-associated Tc decreases in minipigs and monkeys, the minipig revealed a lessened but pronounced QTcaT increase (48 ms). In the monkey, a persistent QTca increase was reduced to only a transient (0.5-3 h) QTcaT increase (20 ms). The dog's lack of THD QTca effects triggered co-administration of atenolol (AT) to attenuate THD-induced HR increases in the dog and monkey. THD + AT revealed peak QTcaT increases of 32 ms in the dog and 40 ms in the monkey, suggesting potential autonomic nervous system (ANS) interference in detecting repolarization changes. These results highlight critical species-specific differences in the outcome of parallel safety investigations. Species selection for nonclinical safety studies should consider the potential impact of Tc and ANS effects to avoid false-negative or overly positive outcomes.

Retinal drug toxicity screening is essential for the development of safe treatment strategies for a large number of diseases. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to the human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single-cell RNA-Seq of retinal organoids indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, digoxin, thioridazine, sildenafil, ethanol, and methanol were selected as key compounds to screen on retinal organoids because of their well-known retinal toxicity profile described in the literature. Exposure of the hPSC-derived retinal organoids to digoxin, thioridazine, and sildenafil resulted in photoreceptor cell death, while digoxin and thioridazine additionally affected all other cell types, including Müller glia cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium. The ability to respond to light was preserved in organoids although the number of responsive retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.

Pharmaceuticals carried into space are subjected to different gravitational conditions. Hypergravity is encountered in the first stage, during spacecraft launching. The stability of medicines represents a critical element of space missions, especially long-duration ones. Therefore, stability studies should be envisaged before the implementation of drugs for future deep space travel, where the available pharmaceuticals would be limited and restocking from Earth would be impossible. Multipurpose drugs should be proposed for this reason, such as phenothiazine derivatives that can be transformed by optical methods into antimicrobial agents. Within this preliminary study, promethazine and thioridazine aqueous solutions were exposed to UV laser radiation that modified their structures and generated a mixture of photoproducts efficient against particular bacteria. Subsequently, they were subjected to 20 g in the European Space Agency's Large Diameter Centrifuge. The aim was to evaluate the impact of hypergravity on the physico-chemical and spectral properties of unirradiated and laser-irradiated medicine solutions through pH assay, UV-Vis/FTIR absorption spectroscopy, and thin-layer chromatography. The results revealed no substantial alterations in centrifuged samples when compared to uncentrifuged ones. Due to their stability after high-g episodes, laser-exposed phenothiazines could be considered for future space missions.

Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major health problem. Drug repurposing coupled to drug combination strategies has been gaining interest among the scientific community. Recently, our group proposed novel drug combinations for breast and colon cancer using repurposed drugs from different classes (antimalarial and central nervous system (CNS)) and chemotherapeutic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), and found promising results. Here, we proposed a novel drug combination using different CNS drugs and doxorubicin (DOX), an antineoplastic used in breast cancer therapy, and studied their anticancer potential in MCF-7 breast cancer cells. Cells were treated with each drug alone and combined with increasing concentrations of DOX and cell viability was evaluated by MTT and SRB assays. Studies were also complemented with morphological evaluation. Assessment of drug interaction was performed using the CompuSyn and SynergyFinder software. We also compiled our previously studied drug pairs and selected the most promising ones for evaluation of the expression of EMT biomarkers (E-cadherin, P-cadherin, vimentin, and β-catenin) by immunohistochemistry (IHC) to assess if these drug combinations affect the expression of these proteins and eventually revert EMT. These results demonstrate that combination of DOX plus fluoxetine, benztropine, and thioridazine at their IC50 can improve the anticancer effect of DOX but to a lesser degree than when combined with PTX (previous results), resulting in most of the drug interactions being antagonist or additive. This suggests that the choice of the antineoplastic drug influences the success of the drug combination. Collectively, these results also allow us to conclude that antimalarial drugs as repurposed drugs have enhanced effects in MCF-7 breast cancer cells, while combination with CNS drugs seems to be more effective in HT-29 colon cancer cells. The IHC results demonstrate that combination treatments increase E-cadherin expression while reducing P-cadherin, vimentin, and β-catenin, suggesting that these treatments could induce EMT reversal. Taken together, these results could provide promising approaches to the design of novel drug combinations to treat breast and colon cancer patients.

Photosensitizing drug reactions are cutaneous eruptions that occur after exposure to ultraviolet radiation in patients using photosensitizing medications. The reactions can be broadly classified into phototoxic and photoallergic, with the former being much more common and well documented. There is an extensive list of photosensitizing medications, especially in the case of phototoxicity. The most common are amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib, and voriconazole. Most of the medications implicated in photosensitivity share an action spectrum within the ultraviolet A range. Distinguishing between phototoxicity and photoallergy can be difficult, because some clinical overlap exists between the two disorders. It is often done based on pathogenesis, clinical presentation, and diagnosis. Management is similar for both types of reactions, with the gold standard being prevention. This review provides an overview of the photosensitizing drug reactions and highlights the similarities and differences between phototoxicity and photoallergy, as well as other photosensitizing drug reactions in the phototoxicity family including lichenoid reactions and pseudoporphyria.

In pediatric acute myeloid leukemia (AML), fusions involving lysine methyltransferase 2A (KMT2A) are considered hallmarks of aggressive AML, for whom the development of targeted specific therapeutic agents to ameliorate classic chemotherapy and obtain a complete eradication of disease is urgent. In this study, we investigated the antiapoptotic proteins in a cohort of 66 pediatric AML patients, finding that 75% of the KMT2A-r are distributed in Q3 + Q4 quartiles of BCL-2 expression, and KMT2A-r have statistically significant high levels of BCL-2, phospho-BCL-2 S70, and MCL-1, indicating a high anti-apoptotic pathway activation. In an attempt to target it, we tested novel drug combinations of venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, in KMT2A-MLLT3, for being the most recurrent, and KMT2A-AFDN, for mediating the worst prognosis, rearranged AML cell lines. Our screening revealed that both the bromodomain and extra-terminal domain (BET) inhibitor, I-BET151, and kinase inhibitor, sunitinib, decreased the BCL-2 family protein expression and significantly synergized with venetoclax, enhancing KMT2A-r AML cell line death. Blasts t (6; 11) KMT2A-AFDN rearranged, both from cell lines and primary samples, were shown to be significantly highly responsive to the combination of venetoclax and thioridazine, with the synergy being induced by a dramatic increase of mitochondrial depolarization that triggered blast apoptosis. Finally, the efficacy of novel combined drug treatments was confirmed in KMT2A-r AML cell lines or ex vivo primary KMT2A-r AML samples cultured in a three-dimensional system which mimics the bone marrow niche. Overall, this study identified that, by high-throughput screening, the most KMT2A-selective drugs converged in different but all mitochondrial apoptotic network activation, supporting the use of venetoclax in this AML setting. The novel drug combinations here unveiled provide a rationale for evaluating these combinations in preclinical studies to accelerate the introduction of targeted therapies for the life-threatening KMT2A-AML subgroup of pediatric AML.

pH-responsive and CD44 receptor-mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes of PEG-poly(β-amino ester) (PEG-PBAE) micelles (PPM) coated with hyaluronic acid (HA) (HA-coated PPM complex, or HPPMc). Thioridazine (Thz) was loaded into HPPMc with a decent drug loading content. The release results of the drug in vitro showed that Thz was released from the HPPMc, which was stimulated by both the acidic pH and specific enzymes. Cytotoxicity studies on mammospheres (MS) revealed that the toxicity potential of Thz-loaded HPPMc (Thz-HPPMc) at pH 5.5 was better than drug solutions. Compared with that at pH 7.4, a higher cellular uptake of a coumarin-6 (C6)-labeled complex at pH 5.5 was observed, which demonstrated that complexes were efficiently taken up in MS. Meanwhile, free HA competitively inhibited the cellular uptake of HPPMc, which revealed that the uptake mechanism was CD44 receptor-mediated endocytosis. Within the acidic endolysosomal environment, the protonation of PBAE facilitated the escape of the complex from the lysosome and releases the drug. The results of in vivo distribution studies and tumor suppression experiments showed that HPMMc could stay in the tumor site of BALB/c nude mice for a longer period of time, and Thz-HPPMc could significantly improve the tumor-suppressing effect. All these results demonstrated the great potential of the multifunctional nanoparticle system for eliminating CSCs.