Isothiocyanates (R-NCS) are sulphur-containing phytochemicals. The main source are plants of the Brassicaceae family. The best known plant-derived isothiocyanate is sulforaphane that has exhibited anticancer activity in both in vivo and in vitro studies. Recent attempts to expand their use in cancer therapy involve combining them with standard chemotherapeutics in order to increase their therapeutic efficacy. The aim of this paper is to determine the impact of sulforaphane and its natural analog alyssin on the anticancer activity of the well-known anticancer drug 5-fluorouracil. The type of drug-drug interactions was determined in prostate and colon cancer cell lines. Confocal microscopy, western blot and flow cytometry methods were employed to determine the mechanism of cytotoxic and cytostatic action of the combinations. The study revealed that additive or synergistic interactions were observed between 5-fluorouracil and both isothiocyanates, which enhanced the anticancer activity of 5-fluorouracil, particularly in colon cancer cell lines. An increased cytostatic effect was observed in case of alyssin while for sulforaphane the synergistic interaction with 5-fluorouracil involved an intensification of apoptotic cell death.

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

Rising out-of-pocket pressures and renewed attention to financial protection in health systems have intensified interest in how health-financing architecture may shape labour-market vulnerability. This article aims to investigate whether shifts in health-financing regimes, captured as data-driven country-year “states” of the financing mix, are associated with changes in vulnerable employment. An unbalanced annual panel merges OECD health-financing components (government, social insurance, private insurance, voluntary insurance, NPISH, enterprise financing, out-of-pocket and cost-sharing; % of GDP) with World Bank controls (GDP per capita; employment-to-population ratio) and the modelled ILO estimate of vulnerable employment; country–year observations are clustered on financing indicators (k-means) and linked to vulnerable employment using two-way fixed-effects models with country-clustered standard errors, complemented by switchers-only and entry/exit specifications. Relative to the modal social-insurance-dominant state (Cluster 5), the compulsory-private-insurance/high household-burden state (Cluster 6) is associated with higher vulnerable employment (β = 5.802, p < 0.001), a relationship that remains significant among switchers (β = 4.244, p < 0.01). Predicted vulnerable employment equals 21.77 in Cluster 5 versus 27.57 in Cluster 6 (baseline), rising to 34.77 for Cluster 6 when key channels (x3, x7, x8) are added. Entry into Cluster 6 is associated with a short-run decline (β = −1.024, p < 0.01), suggesting that transition dynamics may differ from long-run regime-level differences.

Valerian (Valeriana officinalis L.), passionflower (Passiflora incarnata L.), and ginkgo (Ginkgo biloba L.) are among the most widely used medicinal plants in European phytotherapy, with well-documented traditional use for anxiety, insomnia, cognitive decline, attention-deficit/hyperactivity disorder (ADHD), and Parkinson’s disease. This narrative review critically analyses available clinical, pharmacological, toxicological, and regulatory data on these three species in the context of central nervous system (CNS) disorders. A comprehensive literature search was conducted in PubMed, Scopus, and the Cochrane Library; regulatory documents from the European Medicines Agency (EMA), the European Scientific Cooperative on Phytotherapy (ESCOP), and the World Health Organization (WHO) were also included. Valerian showed the most consistent clinical evidence for an improvement in sleep quality and reduction in anxiety. Passionflower demonstrated anxiolytic and mild sedative effects in several controlled trials. Ginkgo showed clinically relevant benefits in mild cognitive impairment, dementia, and vertigo. All three plants exhibited acceptable safety profiles at the recommended doses; however, significant drug interactions were identified, notably ginkgo’s inhibition of CYP2C19 and antiplatelet effects, and valerian’s potentiation of CNS depressants. Regulatory frameworks across EU member states remain inconsistent. Further high-quality randomized controlled trials with standardized extract characterization are needed.