Elastin-derived peptides (EDPs) affect gene and protein expression in human mesenchymal stem cells (hMSCs) - preliminary study.

During the aging process, elastin is degraded and the level of elastin-derived peptides (EDPs) successively increases. The main peptide released from elastin during its degradation is a peptide with the VGVAPG sequence. To date, several papers have described that EDPs or elastin-like peptides (ELPs) affect human mesenchymal stem cells (hMSCs) derived from different tissues. Unfortunately, despite the described effect of EDPs or ELPs on the hMSC differentiation process, the mechanism of action of these peptides has not been elucidated. Therefore, the aim of the present study was to evaluate the impact of the VGVAPG and VVGPGA peptides on the hMSC stemness marker and elucidation of the mechanism of action of these peptides. Our data show that both studied peptides (VGVAPG and VVGPGA) act with the involvement of ERK1/2 and c-SRC kinases. However, their mechanism of activation is probably different in hMSCs derived from adipose tissue. Both studied peptides increase the KI67 protein level in hMSCs, but this is not accompanied with cell proliferation. Moreover, the changes in the NANOG and c-MYC protein expression and in the SOX2 and POU5F1 mRNA expression suggest that EDPs reduced the hMSC stemness properties and could initiate cell differentiation. The initiation of differentiation was evidenced by changes in the expression of AhR and PPARγ protein as well as specific genes (ACTB, TUBB3) and proteins (ß-actin, RhoA) involved in cytoskeleton remodeling. Our data suggest that the presence of EDPs in tissue can initiate hMSC differentiation into more tissue-specific cells.

Current state of knowledge of triclosan (TCS)-dependent reactive oxygen species (ROS) production.

Triclosan (TCS) is widely used in a number of industrial and personal care products. This molecule can induce reactive oxygen species (ROS) production in various cell types, which results in diverse types of cell responses. Therefore, the aim of the present study was to summarize the current state of knowledge of TCS-dependent ROS production and the influence of TCS on antioxidant enzymes and pathways. To date, the TCS mechanism of action has been widely investigated in non-mammalian organisms that may be exposed to contaminated water and soil, but there are also in vivo and in vitro studies on plants, algae, mammalians, and humans. This literature review has revealed that mammalian organisms are more resistant to TCS than non-mammalian organisms and, to obtain a toxic effect, the effective TCS dose must be significantly higher. The TCS-dependent increase in the ROS level causes damage to DNA, protein, and lipids, which together with general oxidative stress leads to cell apoptosis or necrosis and, in the case of cancer cells, faster oncogenesis and even initiation of oncogenic transformation in normal human cells. The review presents the direct and indirect TCS action through different receptor pathways.

The elastin-derived peptide (VGVAPG) activates autophagy in neuroblastoma (SH-SY5Y) cells via peroxisome proliferator-activated receptor gamma (PPARγ).

Autophagy is a self-degradative process important for balancing the sources of energy and involved in the development of Alzheimer's disease (AD). To date, a number of papers have shown that elastin-derived peptides (EDPs) affect the expression and activation of peroxisome proliferator-activated receptor gamma (PPARγ), which is crucial for the development of AD and autophagy initiation. Therefore, the aim of the present study was to determine whether EDPs with a Val-Gly-Val-Ala-Pro-Gly (VGVAPG) amino acid sequence activate the autophagic process in undifferentiated SH-SY5Y human neuroblastoma cells. Our study is the first to show that EDPs with the VGVAPG sequence initiate the autophagy process in the undifferentiated SH-SY5Y cell line exhibiting a number of features of normal neuroblasts. In particular, we observed in our study that VGAVPG peptide increased ULK1, AKT, PPARγ, and LC3B protein expression. Moreover, our experiments with the agonist (rosiglitazone) and antagonist (GW9662) of PPARγ confirm that the studied EDP acts through the PPARγ pathway affecting mTOR and finally autophagy. Some studies have shown that autophagy disturbances are involved in the development of AD. Therefore, we believe that our study will provide new evidence of the possible involvement of EDPs (especially VGVAPG) in the development of AD.

Role of Ciminalum-4-thiazolidinone Hybrids in Molecular NF-κB Dependent Pathways.

A range of hybrid molecules incorporating the ciminalum moiety in the thiazolidinone ring demonstrate significant anticancer and antimicrobial properties. Therefore, the aim of our study was to evaluate the properties and mechanism of action of two 4-thiazolidinone-based derivatives, i.e., 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (Les-45) and 5-[2-chloro-3-(4-nitrophenyl)-2-propenylidene]-2-(3-hydroxyphenylamino)thiazol-4(5H)-one (Les-247). In our study, we analyzed the impact of Les-45 and Les-247 on metabolic activity, caspase-3 activity, and the expression of genes and proteins related to inflammatory and antioxidant defenses and cytoskeleton rearrangement in healthy human fibroblasts (BJ) and a human lung carcinoma cell line (A549). The cells were exposed to increasing concentrations (1 nM to 100 µM) of the studied compounds for 24 h and 48 h. A decrease in the metabolic activity in the BJ and A549 cell lines was induced by both compounds at a concentration range from 10 to 100 µM. Both compounds decreased the mRNA expression of NRF2 (nuclear factor erythroid 2-related factor 2) and ß-actin in the BJ cells. Interestingly, a significant decrease in the level of NF-κB gene and protein expression was detected in the BJ cell line, suggesting a direct impact of the studied compounds on the inhibition of inflammation. However, more studies are needed due to the ability of Les-45 and Les-247 to interfere with the tubulin/actin cytoskeleton, i.e., a critical system existing in eukaryotic cells.

Comparison of the Antioxidant and Cytoprotective Properties of Extracts from Different Cultivars of Cornus mas L.

Cornus mas L. is a rich source of vitamin C and polyphenols. Due to their health-benefit properties, C. mas L. extracts have been used in, e.g., dermatology and cosmetology, and as a food supplement. Peroxisome proliferator-activated receptor gamma (PPARγ) and its co-activator (PGC-1α) are now suspected to be the main target of active substances from C. mass extracts, especially polyphenols. Moreover, the PPARγ pathway is involved in the development of different diseases, such as type 2 diabetes mellitus (DM2), cancers, skin irritation, and inflammation. Therefore, the aim of the present study was to evaluate the PPARγ pathway activation by the most popular water and ethanol extracts from specific C. mas L. cultivars in an in vitro model of the human normal fibroblast (BJ) cell line. We analyzed the content of biologically active compounds in the extracts using the UPLC-DAD-MS technique and revealed the presence of many polyphenols, including gallic, quinic, protocatechuic, chlorogenic, and ellagic acids as well as iridoids, with loganic acid being the predominant component. In addition, the extracts contained cyanidin 3-O-galactoside, pelargonidin 3-O-glucoside, and quercetin 3-glucuronide. The water-ethanol dark red extract (DRE) showed the strongest antioxidant activity. Cytotoxicity was assessed in a normal skin cell line, and positive effects of all the extracts with concentrations ranging from 10 to 1000 µg/mL on the cells were shown. Our data show that the studied extracts activate the PPARγ/PGC-1α molecular pathway in BJ cells and, through this mechanism, initiate antioxidant response. Moreover, the activation of this molecular pathway may increase insulin sensitivity in DM2 and reduce skin irritation.

Dual mechanism of silver nanoparticle-mediated upregulation of adipogenesis in mouse fibroblasts (3T3-L1) in vitro.

Silver nanoparticles (AgNPs) are widespread in the environment due to the increase in their application e.g. in medicine as part of hard-to-heal wound dressings. Many studies have revealed easy diffusion of AgNPs into deep skin layers through damaged epidermis and contact with e.g. fibroblasts. Therefore, the aim of this study was to evaluate the impact of small-size AgNPs (10 nm) in ppm concentrations on the adipogenesis process in mouse embryo fibroblasts (3T3-L1). The results showed a decrease in the metabolic activity, followed by an increase in the reactive oxygen species (ROS) level in a dose- and time-dependent manner (0-20 ppm). The increased caspase-3 activity was observed only at the highest concentration (20 ppm) of AgNPs. Further analysis showed the ability of the tested NPs to increase the lipid accumulation in adipocytes, similar to ROSI [peroxisome proliferator-activated receptor gamma (PPARγ) agonist], measured by Oil-Red-O staining. Moreover, the analyses evidenced the ability of AgNPs to increase the lipoxygenase activity and malondialdehyde levels, which is probably based on ROS-dependent enhancement of lipid hydroperoxidation. Lastly, a significant increase in the PPARγ, Adiponectin, Resistin, Vegf, and Serpine mRNA expression was shown 6 h after the induction of the differentiation process. Based on the obtained results, it can be concluded that small-size AgNPs increase adipogenesis via ROS- and PPARγ-based mechanisms with potential engagement of crosstalk with the aryl hydrocarbon receptor, which is important due to the widespread application of AgNPs in medicine. However, more studies are needed to elucidate the full mechanism of these NPs in the tested cell model in depth.

Crosstalk between the aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor gamma (PPARγ) as a key factor in the metabolism of silver nanoparticles in neuroblastoma (SH-SY5Y) cells in vitro.

The potential usefulness of silver nanoparticles (AgNPs) in anticancer therapy has been postulated for many years. However, little is known to date about the exact impact of such NPs on intracellular detoxication pathways. Therefore, the aim of this study was to determine the impact of AgNPs on the AhR-PPARγ-CYP1A1 pathway in neuroblastoma (SH-SY5Y) cells. The obtained results showed a decrease in the metabolic activity of the SH-SY5Y cells at the 50 and 100 µg/mL concentrations with an increase in caspase-3 activity. An increase in the intercellular ROS production was observed at the 1 and 10 µg/mL concentrations. The co-treatment of the AgNP-treated cells with the AhR and PPARγ inhibitors abolished the effect of the tested AgNPs in the SH-SY5Y cells. In turn, the CYP1A1 activity assay showed a decrease in this parameter in the AgNP-treated cells. Moreover, the gene expression analysis demonstrated that AgNPs were able to increase the AhR and CYP1A1 mRNA expression and decrease the PPARγ gene expression after the 6-h treatment. In turn, an increase in the AhR and PPARγ protein expression was observed after 24 h. Summarizing, the study shows for the first time that AgNPs with a 5-nm diameter size are able to exert a cytotoxic effect on SH-SH5Y cells in a ROS-dependent manner affect the AhR-PPARγ-CYP1A1 pathway inter alia by inhibiting the activity of CYP1A1. This is important due to given present research approaches using such NPs as enhancer agents in the modern PPARγ inhibitor-based anticancer therapy.

Pyrrolidinedione-thiazolidinone hybrid molecules with potent cytotoxic effect in squamous cell carcinoma SCC-15 cells.

The hybrid heterocyclic molecules are perspective materials in the development of anticancer drugs. Here, the pyrrolidinedione-thiazolidinone hybrid molecules were designed as potent anticancer agents. This study aimed to investigate the cytotoxic effect of three derivatives 1-(4-hydroxyphenyl)-, 1-(4-chlorophenyl)- and 1-(4-bromophenyl)-3-[5-[2-chloro-3-(4-nitrophenyl)prop-2-enylidene]-4-oxo-2-thioxothiazolidine-3-yl]pyrrolidine-2,5-diones (Les-6287, Les-6294, and Les-6328, respectively), their effect on the production of the reactive oxygen species (ROS), apoptosis induction, and expression of genes - PPARγ, AHR, and NRFL2 - whose products are important in metabolism in human tongue squamous cell carcinoma cells of SCC-15 line. The results of resazurin reduction and lactate dehydrogenase (LDH) release assays proved the toxicity of the tested derivatives for the SCC-15 cells. Les-6287, Les-6294, and Les-6328 inhibited the viability of SCC-15 cells with the half-maximal effective concentration (EC50) in the range of 10.18-32.75 µM at 24 and 48 h treatment. These derivatives reduced the metabolism of SCC-15 cells with the half-maximal inhibitory concentration (IC50) of 6.72-39.85 µM at 24 and 48 h treatment. Les-6287, Les-6294, and Les-6328 reduced the metabolism of normal human keratinocytes of HaCaT line murine fibroblasts of Balb/c 3T3 line to a lesser extent. The compounds used in a range from 50 to 100 µM concentrations decreased ROS production in the SCC-15 cells. The derivatives Les-6287 and Les-6328 decreased the level of expression of mRNA of PPARγ, AHR, and NRFL2 genes in these cells at PPARγ siRNA knockdown and without it. Thus, the anticancer effect of studied hybrid pyrrolidinedione-thiazolidinones in the SCC-15 carcinoma cells is accompanied by a reduction of their metabolic activity and ROS level, and increase in caspase 3 activity. However, these changes are not the result of direct interaction of Les-6287, Les-6294, and Les-6328 with the PPARγ molecule.

Suppression of sonic hedgehog pathway-based proliferation in glioblastoma cells by small-size silver nanoparticles in vitro.

Glioblastomas (GBs) are one of the most aggressive and invasive intracranial cancers. Recently, it has been postulated that, among other factors, the hedgehog (HH) pathway may be a key factor in this phenomenon. Moreover, it has been reported that small-size silver nanoparticles (AgNPs) are characterized by a high cytotoxic effect towards GBs. However, their effect on the sonic hedgehog (SHH) pathway has never been demonstrated in any cancer cells. Therefore, the aim of the present study was to evaluate the impact of the anti-proliferative properties of 5-nm AgNPs on the SHH pathway in the GB cell line (U-87MG) in vitro. The results showed a time- and dose-dependent decrease in the metabolic activity in the U-87MG cells treated with AgNPs, with IC50 reaching 30.41 and 21.16 µg/mL after 24 h and 48 h, respectively, followed by an increase in the intracellular reactive oxygen species (ROS) level. The co-treatment of the cells with AgNPs and Robotnikinin (SHH inhibitor) abolished and/or strengthened the effect of AgNPs, especially on the SHH mRNA levels and on the PCNA, PTCH1, Gli1, and SUFU protein levels. Interestingly, no changes in the level of ERK1/2, Akt, and SRC kinase protein expression were detected, suggesting a direct impact of AgNPs and/or ROS on the inhibition of the canonical SHH pathway. However, more studies are needed due to the increase in the mTOR protein expression after the treatment of the cells with AgNPs, as in the Robotnikinin treatment. In conclusion, small-size AgNPs are able to inhibit the proliferation of GB cells in vitro by suppressing the canonical SHH pathway.

Involvement of peroxisome proliferator-activated receptor gamma (PPARγ) and autophagic pathways in the mechanism of action of the tris(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO or TBC) flame retardant in the lung adenocarcinoma (A549) cells in vitro.

Tris(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO or TBC) belongs to the class of novel brominated flame retardants. TBC is relatively easily released from products both during production and use; hence, it has been detected in various environmental samples. It has also been reported that TBC causes toxic effects in different cell types and now its mechanism of action is connected with oxidative stress. However, the molecular mechanism of the TBC action is mostly unknown. The aim of this study was to determine the involvement of the PPARγ receptor and certain autophagic proteins (mTOR and p62) in the mechanism of the TBC action in adenocarcinomic human alveolar basal epithelial cells (A549) in vitro. Our study showed that TBC induced toxicity only at the highest micromolar concentrations (10, 50, and 100 µM) in human A549 cells, which are a well-established model of the alveolar type II pulmonary epithelium. TBC probably induced apoptosis only at the 50- and 100-µM concentrations. However, in our experimental model, TBC showed the ability to trigger oxidative stress and affected the mRNA expression of antioxidant enzymes (SOD1 and CAT) at the lower concentrations (1 and 10 µM) than in the case of apoptosis, suggesting that the apoptosis was ROS independent. Our experiments with the PPARγ agonist (rosiglitazone) and antagonist (GW9662) suggests that TBC acted in the A549 cell line probably through activation of the mTOR-PPARγ pathway and could interfere with the p62 autophagy pathway.

Disruption of neurosteroid synthesis and release by tris(2,3-dibromopropyl)isocyanurate in primary mouse cortical astrocytes in vitro.

Neurosteroidogenesis in astrocytes is crucial for the proper development and functioning of the brain. During this process, key neurohormones such as progesterone (P4 ), testosterone (T), and estradiol (E2 ) are produced. Proper production and release of neurosteroids can be affected by substances referred to as endocrine-disrupting compounds (EDCs). Tris-(2,3-dibromopropyl)isocyanurate (TBC) is a representative of novel brominated flame retardants used to stop ignition or reduce fire-related property damage to plastics, polyolefin, polyphenyl alkene, unsaturated polyester, synthetic rubber, and fibers. Interestingly, previous studies have shown that TBC can enhance the proliferation of estradiol-sensitive breast cancers in vitro, which suggests that TBC has EDC properties. Therefore, given the suspected endocrine-disrupting properties of TBC, the aim of the present study was to determine the impact of TBC on the neurosteroid (P4 , T, and E2 ) production and secretion as well as the mRNA expression of key enzymes involved in its production in mouse astrocytes in vitro. Our paper shows that TBC increases P4 production with a strong decrease in T production, which is accompanied by a decrease in Cyp17a1 mRNA expression, that is, the main enzyme metabolizing P4 to T. Moreover, TBC in both studied concentrations increases P4 secretion in the culture medium. Finally, our studies have demonstrated an increase in the expression of Cyp19a1 mRNA, an enzyme metabolizing T to E2 , with a simultaneous increase in the amount of E2 in cells. Our data clearly show that TBC in an in vitro environment acts as EDCs, which may lead to serious consequences for the proper development and functioning of the brain.

Reprotoxic Effect of Tris(2,3-Dibromopropyl) Isocyanurate (TBC) on Spermatogenic Cells In Vitro.

Tris(2,3-dibromopropyl) isocyanurate (TBC) belongs to the class of novel brominated flame retardants (NFBRs) that are widely used in industry. It has commonly been found in the environment, and its presence has been discovered in living organisms as well. TBC is also described as an endocrine disruptor that is able to affect male reproductive processes through the estrogen receptors (ERs) engaged in the male reproductive processes. With the worsening problem of male infertility in humans, a mechanism is being sought to explain such reproductive difficulties. However, so far, little is known about the mechanism of action of TBC in male reproductive models in vitro. Therefore, the aim of the study was to evaluate the effect of TBC alone and in cotreatment with BHPI (estrogen receptor antagonist), 17ß-estradiol (E2), and letrozole on the basic metabolic parameters in mouse spermatogenic cells (GC-1 spg) in vitro, as well as the effect of TBC on mRNA expression (Ki67, p53, Pparγ, Ahr, and Esr1). The presented results show the cytotoxic and apoptotic effects of high micromolar concentrations of TBC on mouse spermatogenic cells. Moreover, an increase in Pparγ mRNA levels and a decrease in Ahr and Esr1 gene expression were observed in GS-1spg cells cotreated with E2. These results suggest the significant involvement of TBC in the dysregulation of the steroid-based pathway in the male reproductive cell models in vitro and may be the cause of the currently observed deterioration of male fertility. However, more research is needed to reveal the full mechanism of TBC engagement in this phenomenon.

Epidermal Growth Factor-labeled liposomes as a way to target the toxicity of silver nanoparticles into EGFR-overexpressing cancer cells in vitro.

Silver nanoparticles (AgNPs) are the most toxic nanostructures for both cancer and healthy cells. Thus, their usefulness in the anticancer therapy is limited. Interestingly, the epidermal growth factor receptor (EGFR) is overexpressed in many cancer cells, e.g. in lung and tongue cancers. Therefore, the aim of this study was to develop a way to direct the cytotoxic effect of AgNPs against cancer cells, saving healthy ones by entrapping these NPs inside liposomes labeled with the epidermal growth factor (EGF-LipoAgNPs) and directing these structures into EGFR-overexpressing cancer cells. The obtained results showed spherical structures with a 107.9 nm size and - 16.60 mV zeta-potential. The UV-Vis scan and TEM images did not show free AgNPs in the solution. The obtained complexes were able to decrease the metabolic activity in the A549 and SCC-15 cells more effectively than native AgNPs. Furthermore, the ROS production, lactate dehydrogenase release, and caspase-9 and -3 activity were significantly increased after the treatment with EGF-LipoAgNPs for 24 and 48 h. The expression of genes encoding catalase, superoxide dismutase, and p53 protein increased significantly, while the KI67 gene expression decreased, especially in the A549 and SCC-15 cells. Moreover, the KI67 protein expression was lower than in the cells treated with native AgNPs, while catalase activity was decreased significantly after the treatment with the obtained complexes. In turn, SOD activity increased more efficiently in the EGFR-overexpressing cancer cells. In all tested parameters, EGF-LipoAgNPs exerted a lower toxic effect on the BJ cells than native AgNPs. Summarizing, the created liposomal system reduces the toxicity of AgNPs against normal human fibroblasts and enhances the toxic and proapoptotic effect of these NPs, which may be caused by improvement of their uptake by EGFR-overexpressing cancer cells.

Elastin-Derived Peptides in the Central Nervous System: Friend or Foe.

Elastin is one of the main structural matrix proteins of the arteries, lung, cartilage, elastic ligaments, brain vessels, and skin. These elastin fibers display incredible resilience and structural stability with long half-life. However, during some physiological and pathophysiological conditions, elastin is prone to proteolytic degradation and, due to the extremely low turnover rate, its degradation is practically an irreversible and irreparable phenomenon. As a result of elastin degradation, new peptides called elastin-derived peptides (EDPs) are formed. A growing body of evidence suggests that these peptides play an important role in the development of age-related vascular disease. They are also detected in the cerebrospinal fluid of healthy people, and their amount increases in patients after ischemic stroke. Recently, elastin-like polypeptides have been reported to induce overproduction of beta-amyloid in a model of Alzheimer's disease. Nevertheless, the role and mechanism of action of EDPs in the nervous system is largely unknown and limited to only a few studies. The article summarizes the current state of knowledge on the role of EDPs in the nervous system.

New 4-thiazolidinone-based molecules Les-2769 and Les-3266 as possible PPARγ modulators.

Development of cancer drug-resistance is still an ongoing problem in the modern anticancer treatment. Therefore, there is a need to search for a new active substance, which may become a potential anticancer agent. 4-Thiazolidinones are well-described substances with cytotoxicity against cancer cells in vitro. Therefore, the aim of this study was to evaluate the effect of two 4-thiazolidinone-based derivatives (Les-2769 and Les-3266) on the PPARγ-dependent cytotoxicity in normal human skin fibroblasts (BJ) and squamous cell carcinoma (SCC-15) in vitro. The data obtained showed a cytotoxic effect of Les-2769 and Les-3266 used in micromolar concentrations on SCC-15 and BJ cells, manifesting by a decrease in the metabolic activity, an increase in the release of lactate dehydrogenase, and caspase-3 activity. The co-treatment of the cells with Les-3266 and an antagonist (GW9662) or an agonist (rosiglitazone) of the PPARγ receptor induced changes in the above-mentioned parameters in the BJ and SCC-15 cells, compared to the Les-3266 alone exposure; this was not found in the Les-2769-treated cells. The further analysis of the compounds indicated changes in the expression of the PPARγ, KI67, and NF-κB genes. Moreover, the tested compounds caused an increase in the level of PPARγ mRNA expression in a similar way to rosiglitazone in SCC-15, which may indicate the affinity of the compounds for PPARγ. Molecular docking is consistent with experimental in vitro data about the potential agonistic activity of Les-2769 and Les-3266 towards PPARγ receptors. Summarizing, the anticancer effect of both compounds was observed in the SCC-15 cells in vitro; moreover, the mechanism of action of Les-3266 in cells is mediated probably by interaction with the PPARγ receptor pathway, which needs in-depth study.

Involvement of sirtuins (Sirt1 and Sirt3) and aryl hydrocarbon receptor (AhR) in the effects of triclosan (TCS) on production of neurosteroids in primary mouse cortical neurons cultures.

Epidemiological studies have shown the presence of triclosan (TCS) in the brain due to its widespread use as an antibacterial ingredient. One of the confirmed mechanisms of its action is the interaction with the aryl hydrocarbon receptor (AhR). In nerve cells, sirtuins (Sirt1 and Sirt3) act as cellular sensors detecting energy availability and modulate metabolic processes. Moreover, it has been found that Sirt1 inhibits the activation of estrogen receptors, regulates the androgen receptor, and may interact with the AhR receptor. It is also known that Sirt3 stimulates the production of estradiol (E2) via the estradiol receptor ß (Erß). Therefore, the aim of the present study was to evaluate the effect of TCS alone or in combination with synthetic flavonoids on the production of neurosteroids such as progesterone (P4), testosterone (T), and E2 in primary neural cortical neurons in vitro. The contribution of Sirt1 and Sirt3 as well as AhR to these TCS-induced effects was investigated as well. The results of the experiments showed that both short and long exposure of neurons to TCS increased the expression of the Sirt1 and Sirt3 proteins in response to AhR stimulation. After an initial increase in the production of all tested neurosteroids, TCS acting for a longer time lowered their levels in the cells. This suggests that TCS activating AhR as well as Sirt1 and Sirt3 in short time intervals stimulates the levels of P4, T, and E2 in neurons, and then the amount of neurosteroids decreases despite the activation of AhR and the increase in the expression of the Sirt1 and Sirt3 proteins. The use of both the AhR agonist and antagonist prevented changes in the expression of Sirt1, Sirt3, and AhR and the production of P4, T, and E2, which confirmed that this receptor is a key in the mechanism of the TCS action.

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives.

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be a basis for the search for new potential drugs. Therefore, the aim of this study was to evaluate the cytotoxic, cytostatic, and antibacterial effects of certain 4-thiazolidinone-based derivatives, Les-3166, Les-5935, Les-6009, and Les-6166, on human fibroblasts (BJ), neuroblastoma (SH-SY5Y), epithelial lung carcinoma (A549), and colorectal adenocarcinoma (CACO-2) cell lines in vitro. All tested compounds applied in a concentration range from 10 to 100 µM were able to decrease metabolic activity in the BJ, A549, and SH-SY5Y cell lines. However, the action of Les-3166 was mainly based on the ROS-independent pathway, similarly to Les-6009. In turn, Les-5935 and Les-6166 were able to promote ROS production in BJ, A549, and SH-SY5Y cells, compared to the control. Les-3166, Les-6009, and Les-6166 significantly increased the caspase-3 activity, especially at the concentrations of 50 µM and 100 µM. However, Les-5935 did not induce apoptosis. Only Les-5935 showed a minor cytostatic effect on SH-SY5Y cells. Additionally, the antibacterial properties of the tested compounds against P. aeruginosa bacterial biofilm can be ranked as follows: Les-3166 > Les-5935 > Les-6009. Les-6166 did not show any anti-biofilm activity. In summary, the study showed that Les-5935, Les-6009, and Les-6166 were characterized by anticancer properties, especially in the human lung cancer cell. In cases of BJ, SH-SY5Y, and CACO-2 cells the anticancer usage of such compounds is limited due to effect visible only at 50 and 100 µM.

Comprehensive review of the impact of tris(2,3-dibromopropyl) isocyanurate (TBC or TDBP-TAZTO) on living organisms and the environment.

Tris(2,3-dibromopropyl) isocyanurate (TBC or TDBP-TAZTO) belongs to the group of brominated flame retardants (BFRs). The production of this compound is increasing due to the growing demand and wide application in electrical, electronic, musical instrument, and automotive component industries. The properties of TBC, e.g., the high octanol-air partition coefficient (Koa), high octanol-water partition coefficient (Kow), and high bioconcentration factor (BCF), indicate a possibility of its spread in aquatic and terrestrial ecosystems and bioaccumulation in living organisms. The presence of TBC has been confirmed in soil, sediments, river water, and such materials as microplastic, curtains, and e-waste devices. The compound has potential to bioaccumulate in the food chain of living organisms. TBC has been demonstrated to exert a harmful effect mainly on the nervous and endocrine systems, lungs, and liver. The possible mechanism of toxicity of the compound in the nervous system is based on the generation of oxidative stress by TBC leading to apoptosis of neuronal cells, while mitochondrial damage is considered to be responsible for changes in the respiratory organ. Moreover, the potential of mussels and earthworms to be bioindicators of TBC has been proven. Therefore, the literature review is focused on TBC properties and analysis of the identification and impact of the compound on the environment, living organisms, and human cell lines. Given the many toxic effects of TBC highlighted in the literature, there is a need for more profound research on the safety of TBC and methods for identification and degradation of this compound.

Paracetamol - An old drug with new mechanisms of action.

Paracetamol (acetaminophen) is the most commonly used over-the-counter (OTC) drug in the world. Despite its popularity and use for many years, the safety of its application and its mechanism of action are still unclear. Currently, it is believed that paracetamol is a multidirectional drug and at least several metabolic pathways are involved in its analgesic and antipyretic action. The mechanism of paracetamol action consists in inhibition of cyclooxygenases (COX-1, COX-2, and COX-3) and involvement in the endocannabinoid system and serotonergic pathways. Additionally, paracetamol influences transient receptor potential (TRP) channels and voltage-gated Kv7 potassium channels and inhibits T-type Cav3.2 calcium channels. It also exerts an impact on L-arginine in the nitric oxide (NO) synthesis pathway. However, not all of these effects have been clearly confirmed. Therefore, the aim of our paper was to summarize the current state of knowledge of the mechanism of paracetamol action with special attention to its safety concerns.

Possibility to Biotransform Anthracyclines by Peroxidases Produced by Bjerkandera adusta CCBAS 930 with Reduction of Geno- and Cytotoxicity and Pro-Oxidative Activity.

The aim of this study was to evaluate the bioremoval mechanism of anthracycline antibiotics by the white-rot fungus B. adusta CCBAS 930. The activity of oxidoreductases and levels of phenolic compounds and free radicals were determined during the biotransformation of anthraquinone antibiotics: daunomycin (DNR) and doxorubicin (DOX) by B. adusta strain CCBAS 930. Moreover, phytotoxicity (Lepidium sativum L.), ecotoxicity (Vibrio fischeri), genotoxicity and cytotoxicity of anthraquinone dyes were evaluated before and after biological treatment. More than 80% and 90% of DNR and DOX were removed by biodegradation (decolorization). Initial solutions of DNR and DOX were characterized by eco-, phyto-, geno- and cytotoxicity. Despite efficient decolorization, secondary metabolites, toxic to bacteria, formed during biotransformation of anthracycline antibiotics in B. adusta CCBAS 930 cultures. DNR and DOX metabolites did not increase reactive oxygen species (ROS) production in human fibroblasts and resazurin reduction. DNR metabolites did not change caspase-3 activity.