Evaluation of developmental toxicity in zebrafish embryos and antiproliferative potential against human tumor cell lines of new derivatives containing 4-nitrophenyl group.

The aim of the studies was to evaluate the antiproliferative potential against human tumor cell lines of newly synthetized derivatives containing 4-nitrophenyl group, as well as its impact on developmental toxicity in zebrafish model. We selected 1-(4-nitrobenzoyl)-4-ethylsemicarbazide (APS-1) and 1-[(4-nitrophenyl)acetyl]-4-hexyl-thiosemicarbazide (APS-18) for research. The antiproliferative properties of semicarbazide derivatives were assessed against human cancer cell lines derived from hepatocellular adenocarcinoma (HepG2), renal cell carcinoma (769-P), non-small cell lung cancer (NCI-H1563) and glioblastoma multiforme (LN229) in comparison to the physiological human embryonic kidney (HEK-293) cell line. The influence of the tested substances on the cell cycle and apoptosis was also evaluated. Fish embryo acute toxicity test (FET) was performed based on OECD Guidelines (Test No. 236), and was carried out for the first 5 days post fertilization. The following concentrations of APS-1 and APS-18 were tested: 125-2000 µM and 0.125-1000 µM, respectively. The presented studies on the antiproliferative properties of the new semicarbazide derivatives showed that the compounds APS-1 and APS-18 reduce the viability of human tumor lines. Particularly noteworthy is the strong and selective antiproliferative activity of APS-18 against all neoplastic cell lines, in particular against glioblastoma. Against this tumor line, the compound APS-1 showed an effective inhibitory effect. In the FET we noted that the direct exposure of zebrafish embryos to APS-1 and APS-18 in used range of concentration did not cause morphological abnormalities, including cardiotoxicity. On basis of obtained outcomes it could be concluded that APS-1 and APS-18 may constitute models for further research, design and synthesis of new, safer drugs with more favorable anticancer properties.

1,2,4-Triazolin-5-thione derivatives with anticancer activity as CK1γ kinase inhibitors.

The optimization and synthesis of new CK2 and CK1 inhibitors are the basis for the development of new therapeutic strategies for the treatment of cancer and neurodegenerative disorders associated with overexpression and abnormal functioning of these enzymes. Triazole derivatives appear to be especially interesting as potential kinase inhibitors. In this context we synthesized a series of 1,2,4-triazolin-5-thione derivatives as CK1γ kinase inhibitors. The antiproliferative activity of synthesized compounds was assessed against cancer cells: human lung adenocarcinoma (A549), human hepatoma (HepG2), and human breast adenocarcinoma (MCF-7). Compound 1 exhibited antiproliferative potency against A549 cancer cells and was characterized by a selective antiproliferative effect. Additionally, this compound has high apoptotic activity against A549, HepG2, MCF-7 cells and induced only slight amount of necrotic cells in these cell lines. In order to decipher the mechanism of anticancer activity of the studied compounds PASS software was used and these compounds were assayed for the inhibition of CK1γ and CK2α kinases. The reported series of 1,2,4-triazolin-5-thiones inhibits CK1γ and CK2α kinases in micromolar range. The most active compound shows activity against isoform γ3 which at concentration of 50 µM reduced the kinase activity by 69% while at 100 µM by 80%. CK2α was found to be less susceptible to the effects of the triazoles tested, as the reduction in kinase activity by 29% was observed for compound 15, and by 27% for compound 1 only at the concentration of 100 µM. The inhibition of CK1γ and CK2α kinases was rationalized using molecular docking.

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies.

A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures for analyzed 1,2,4-triazol-5-thione derivatives. The conformational preferences resulting from rotational degrees of freedom of the 1,2,4-triazole ring substituents were characterized. The lipophilicity (logP) and electronic parameters as the energy of frontier orbitals, dipole moments, NBO net charge distribution on the atoms, and electrostatic potential distribution for all structures were calculated at AM1 and DFT/B3LYP/6-311++G(d,p) level. The in vitro test was done against M. tuberculosis H37Ra, M. phlei, M. smegmatis, and M. timereck. The obtained results clearly confirmed the antituberculosis potential of compound C4, which turned out to be the most active against Mycobacterium H37Ra (MIC = 0.976 µg/mL), Mycobaterium pheli (MIC = 7.81 µg/mL) and Mycobacerium timereck (62.6 µg/mL). Satisfactory results were obtained with compounds C8, C11, C14 versus Myc. H37Ra, Myc. pheli, Myc. timereck (MIC = 31.25-62.5 µg/mL). The molecular docking studies were carried out for all investigated compounds using the Mycobacterium tuberculosis cytochrome P450 CYP121 enzyme as molecular a target connected with antimycobacterial activity.

Synthesis and Antioxidant Activity of New Norcantharidin Analogs.

New norcantharidin analogs were designed and obtained as compounds with biological activity. As a starting material, exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid anhydride was used. Three groups of compounds: dicarboximides, triazoles and thiazolidines were obtained in multistep reactions. The 1 H- and 13 C-NMR spectra were used to confirm the structures of all obtained products and they were in agreement with the proposed structure of substances. All derivatives were screened for their antioxidant activity. The most promising group was dicarboximides (1-4, 6). Derivatives 2-4 displayed antioxidant activity with EC50 =7.75-10.89 µg/ml, which may be comparable to strong antioxidant Trolox (EC50 =6.13 µg/ml). Excellent activity with EC50 =10.75 µg/ml also presented norcantharidin analog with 1,2,4-triazole system (12).

Rs10887800 renalase gene polymorphism influences the level of circulating renalase in patients undergoing hemodialysis but not in healthy controls.

BACKGROUND: Human renalase (RNLS), a recently identified flavoprotein with oxidoreductase activity, is secreted into blood by kidneys and metabolizes circulating catecholamines. Recent studies have revealed that common polymorphisms in RNLS gene might affect the risk of several cardiovascular conditions in hemodialyzed patients. However, the exact mechanism underlying this link remains unclear. The study aims to investigate the association between RNLS gene polymorphisms and plasma renalase level in ESKD patients undergoing hemodialysis (HD group) and healthy controls (HC). METHODS: A total of 309 hemodialyzed patients and 90 controls were enrolled in the study. All the participants were genotyped for two RNLS SNPs (rs2576178 and rs10887800) using PCR-RFLP method. Plasma renalase concentrations were determined by enzyme-linked immunosorbent assay (USCN Life Science Inc., Wuhan, China). The IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, NY, USA) was used for statistical analyses. RESULTS: Genotype distribution and allele frequencies of studied SNPs did not differ between two analyzed groups, p > .050. RNLS concentration in HD group (33.54 µg/mL) was significantly higher than in HC (13.16 µg/mL), p < .001. HD patients with rs10887800AA genotype had lower renalase level (29.32 µg/mL) compared to those with AG (34.52 µg/mL), p < .010 and GG genotype (35.91 µg/mL), p < .010. No significant differences in plasma RNLS between rs10887800AG and GG carriers were observed, p > .050. Interestingly, in HC group rs10887800 polymorphism did not influence RNLS concentration. Rs2576178 SNP did not affect the level of plasma RNLS either in HD group or in HC. CONCLUSION: Rs10887800 polymorphic variant of RNLS gene influences the level of circulating RNLS in patients undergoing hemodialysis, and thus elucidates the potentially functional relevance of this polymorphism in HD population.

A review of exposure and toxicological aspects of carbon nanotubes, and as additives to fire retardants in polymers.

Carbon nanotubes (CNTs) have attracted considerable interest due to their unique physical, chemical, optical and electrical properties opening avenues for a large number of industrial applications. They have shown potential as fire retardant additives in polymers, reducing heat release rate and increasing time to ignition in a number of polymers. Relevant work on the types, properties and applications has been reviewed particularly considering their application in fire situations. There are concerns over the health risks associated with CNTs and many papers have likened CNTs to the health problems associated with asbestos. There are contradictions relating to the toxicity of CNTs with some papers reporting that they are toxic while others state the opposite. Directly comparing various studies is difficult because CNTs come in many combinations of size, type, purity levels and source. CNTs can potentially be released from polymers during the combustion process where human exposure may occur. While this review has shed some light regarding issues relating to toxicity under different fire scenarios much more thorough work is needed to investigate toxicity of CNTs and their evolution from CNT-polymer nanocomposites in order to reach firm conclusions.

Synthesis, antibacterial and antiproliferative potential of some new 1-pyridinecarbonyl-4-substituted thiosemicarbazide derivatives.

In this study, the antibacterial, cytotoxic and antiproliferative activities of novel thiosemicarbazide derivatives were assessed. Our results demonstrated that some of the novel compounds possess good antibacterial properties against Staphylococcus epidermidis, Streptococcus mutans and Streptococcussanguinis and are only slightly cytotoxic; thus, they exhibit an excellent therapeutic index, which is higher than that of ethacridine lactate. Moreover, our data showed that compounds 2 and 4 have an antiproliferative activity against human breast adenocarcinoma and human hepatocellular carcinoma cell lines. We expect that the novel thiosemicarbazide derivatives can be used as agents for treatment of dental caries and also for chemotherapy support.

[Acquired perforating dermatosis in the patient with chronic kidney disease ­ case report and literature review].

Acquired perforating dermatosis (APD) represents a heterogenous group of skin disorders characterized histopathologically by transepithelial elimination (TEE) of dermal structures. APD is manifested clinically as multi-localized, papulo-nodular skin lesions accompanied by a refractory pruritus. APD typically coexists with long-term disorders, most often diabetic kidney disease (DKD). The paper presents a case of a 56-year-old male patient with chronic kidney disease (CKD) and concomitant acquired reactive perforating collagenosis (ARPC), which is a subtype of APD. Etiological theories of ARPC as well as current diagnostic and treatment principles in dermatosis were described. On the basis of the presented case report and the literature review attention was paid to diagnostic difficulties associated with APD. The assumption was made that APD can be an underdiagnosed disease and thus it is not treated correctly. According to the authors' opinion, this is an important circumstance to popularize the knowledge about APD.

New Norcantharidin Analogs: Synthesis and Anticancer Activity.

The reaction of direct condensation between S-ethyl-N-(7-oxabicyclo-[2.2.1]heptane-2,3-dicarbonyl)isothiosemicarbazide (1) and primary amines was used for synthesizing new N-substituted amides of 3-(3-ethylthio-1,2,4-triazol-5-yl)-7-oxabicyclo-[2.2.1]heptane-2-carboxylic acid (2-12) as norcantharadin analogs. Moreover, the anticancer activity of the obtained compounds was studied. Among all compounds, the N-3-methylbutyl amide of 3-(3-ethylthio-1,2,4-triazol-5-yl)-7-oxabicyclo-[2.2.1]heptane-2-carboxylic acid (4) presented selective in vitro toxic and antiproliferative effects against the human hepatoma cell line Hep3B, without affecting normal human liver stellate cells (LX-2 cell line).

Retention-property relationships of 1,2,4-triazoles by micellar and reversed-phase liquid chromatography.

The properties of 21 1,2,4-triazoles, relevant to their pharmacokinetics, were investigated using experimental methods and in silico calculations. The lipophilicities of the compounds were determined experimentally using reversed-phase chromatography and liquid chromatography with micellar mobile phases, or they were calculated in silico from their molecular structures. In the reversed-phase technique, an octadecylsilyl, immobilized artificial membrane and immobilized cholesterol were used as the stationary phases. Biological descriptors of compounds, i.e. log BB, log KHSA, Caco-2, and fu,brain, were determined in silico by using ACD/Percepta software. Principal component analysis was used to indicate similarities between chromatographic, partitioning, and biological variables. Highly significant relationships were determined to exist between the chromatographic parameters and the biological descriptors, especially for log BB and log KHSA. The chromatographic parameters measured on the cholesterol column were recommended for use in predicting the lipophilic and biological properties of the 1,2,4-triazoles that were tested.

Newly synthesized derivatives with a thiosemicarbazide group reduce the viability of cancer cell lines. Acute toxicity assessment in Zebrafish (Danio rerio) early life stages.

Due to the variability and ability of tumor to mutate, as well as the heterogeneity of tumor tissue, such drugs are sought that would act selectively and multidirectionally on the cancer cell. Therefore, two newly synthesized semicarbazide structured substances were evaluated for anticancer properties in our study: 1a and 1b. In order to evaluate the cytotoxicity and selectivity of the tested compounds, MTT and Neutral Red uptake assay on cell lines (HEK293, LN229, 769-P, HepG2 and NCI-H1563) and cell cycle analysis were performed. Acute toxicity and cardiotoxicity were also evaluated in the zebrafish model. The tested compounds (1a, 1b) showed cytotoxic activity, with the greatest selectivity noted against the glioblastoma multiforme cell line (LN229). However, compound 1b showed stronger selective activity than 1a. Both of compounds were shown to significantly affect the M phase of the cell cycle. Whereas, the conducted toxicological examination of newly synthesized thiosemicarbazide derivates showed, that direct exposition of Danio rerio embryos to compound 1a, but not 1b, causes a concentration-dependent increase in developmental malformations, indicating possible teratogenic effects.

Assessment of cytokine release after in vitro stimulation of whole blood with legionella pneumophila in immunocompromised patients.

This study we examined ex vivo potential of the immune response after stimulation of whole blood with L. pneumophila SG 1, SG 2-14 and L. pneumophila standard strain ATCC 33152 in immunocompromised patients, such as: hemodialysis patients and patients after renal transplantation. The levels of TNF-α and IFN-γ in supernatants were measured with the use of commercial ELISA kits. The synthesis of TNF-α and IFN-γ after stimulation with L. pneumophila were analyzed in two aspects: differentiated stimulatory activity in relation to SG 1, SG 2-14 and ATCC 33152 L. pneumophila and differentiated response of the hemodialysis patients and patients after renal transplantation in relation to the control group. The positive and negative results of anti-L. pneumophila antibodies of two groups of our patients were found for the analysis of the stimulatory activity of L.pneumophila as a primary or secondary response. In patients with immunosuppression the response in the secretion of cytokines (TNF-α and IFN-γ) was reduced after stimulation of L. pneumophila SG 1 but in varying degrees after stimulation of L. pneumophila SG 2-14, which indicates that the risk of the infection is varied.

3-Benzyl-4-ethyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C(11)H(13)N(3)S, exists in the 5-thioxo tautomeric form. The benzene ring exhibits disorder with a refined ratio of 0.77 (2):0.23 (2) for components A and B with a common bridgehead C atom. The 1,2,4-triazole ring is essentially planar, with a maximum deviation of 0.002 (3) Šfor the benzyl-substituted C atom, and forms dihedral angles of 88.94 (18) and 86.56 (49)° with the benzene rings of components A and B, respectively. The angle between the plane of the ethyl chain and the mean plane of 1,2,4-triazole ring is 88.55 (15)° and this conformation is stabilized by an intra-molecular C-H⋯S contact. In the crystal, pairs of N-H⋯S hydrogen bonds link mol-ecules into inversion dimers. π-π inter-actions are observed between the triazole and benzene rings, with centroid-centroid separations of 3.547 (4) and 3.544 (12) Šfor components A and B, and slippages of 0.49 (6) and 0.58 (15) Å, respectively.

Contamination of UK firefighters personal protective equipment and workplaces.

Firefighters' personal protective equipment (PPE) is a potential source of chronic exposure to toxic contaminants commonly released from fires. These contaminants have also been found in fire stations. However, little research characterises the routes via which fire contaminants travel back to fire stations. The UK Firefighter Contamination Survey provides information on firefighters' PPE provision, decontamination, and storage practices. All serving UK firefighters were eligible to take part in the survey, which comprised 64 questions. A total of 10,649 responses were included for analysis, accounting for roughly 24% of the UK's firefighting workforce. Results revealed that most firefighters (84%) de-robe contaminated PPE/workwear after re-entering the appliance cab. There was a significant decreasing tendency to send PPE for cleaning after every incident with increasing seniority of role, length of service, and fire attendance frequency. Around one third of firefighters cleaned PPE after every incident. A number of issues were linked to external professional cleaning services, e.g. shrinkage, fit, turn-around time, and stock of reserve/pooled PPE. PPE storage was found to be a potential source of cross contamination, with almost half of firefighters (45%) indicating clean and dirty PPE is not stored separately. More than half of firefighters (57%) stored fire gloves (an item sent for professional decontamination by only 19% of firefighters, and never cleaned by 20%) within other items of PPE such as helmets, boots and tunic/trouser pockets. The survey's results can be used to target gaps in decontamination measures within UK Fire and Rescue Services.

Mental health of UK firefighters.

Exposure to trauma, high-stress situations, and disrupted sleep are well known risk factors affecting firefighters' mental health. Little is known about the association between firefighters' exposure to fire contaminants and mental health disorders. The UK Firefighter Contamination Survey assessed firefighters' health and capacity for occupational exposure to contaminants. Participants were invited to anonymously complete its 64 questions online. Logistic regression analyses assessed the associations between self-reported mental health disorders and proxies of contaminant exposure. Results found that firefighters who notice soot in their nose/throat for more than a day after attending fires (Odds Ratio (OR) = 1.8, 1.4-2.4), and those who remain in their personal protective equipment (PPE) for over 4 h after fires (OR = 1.9, 1.2-3.1), were nearly twice as likely to report mental health disorders. Significantly increased odds ratios for all three outcomes of interest (anxiety, depression and/or any mental health disorders) were also found among firefighters who take PPE home to clean. Sleeping problems were reported by 61% of firefighters. These firefighters were 4.2 times more likely to report any mental health disorder (OR = 4.2, 3.7-4.9), 2.9 times more likely to report anxiety (OR = 2.9, 2.4-3.5) and 2.3 times more likely to report depression (OR = 2.3, 1.9-2.8) when compared to firefighters who did not report sleep issues. Effective decontamination measures within UK Fire and Rescue Services, together with firefighters' wellness, may play a crucial role in protecting firefighters' mental health.

Cancer incidence amongst UK firefighters.

Firefighters suffer an increased risk of cancer from exposures to chemicals released from fires. Our earlier research has found that fire toxicants not only remain on firefighters' PPE, but are also tracked back to fire stations. The UK Firefighter Contamination Survey assesses firefighters' risk of developing cancer due to occupational exposure to fire toxins. Over 4% of surveyed firefighters were found to have a cancer diagnosis, with the age-specific cancer rate up to 323% higher (35-39 year olds) than that of the general population. Firefighters who had served ≥ 15 years were 1.7 times more likely to develop cancer than those who had served less time. Firefighters were at least twice as likely to be diagnosed with cancer if they noticed soot in their nose/throat (odds ratio (OR) = 2.0, 1.1-3.5), or remained in their PPE for more than four hours after attending a fire incident (OR = 2.3, 1.1-5.2). Also associated with an increased likelihood of cancer was: eating while wearing PPE (OR = 1.8, 1.2-2.7); failing to store clean/dirty PPE separately (OR = 1.3, 1.0-1.7); working in a station that smells of fire (OR = 1.3, 1.0-1.8) or not having designated (separated) clean and dirty areas (OR = 1.4, 1.1-1.7); using an on-site washing machine to launder fire hoods (OR = 1.3, 1.0-1.7); feeling that cleaning is not taken seriously at work (OR = 1.5, 1.2-2.0).

Culture and awareness of occupational health risks amongst UK firefighters.

Firefighters are exposed to toxic chemicals not only from the fire incidents they attend, but also from their contaminated station and/or personal protective equipment (PPE). Little is currently known about firefighters' awareness, attitudes, and behaviours towards contaminants which was assessed in the UK firefighter contamination survey. Results revealed that lack of training on fire effluents and their health outcomes are strongly associated with increased fire smoke/contaminant exposure. Notably, untrained firefighters were at least twice as likely to: never clean personal protective equipment (PPE) (Crude Odds Ratio, OR 2.0, 1.5-2.7), infrequently send their PPE for professional cleaning (OR 2.0, 1.6-2.4), remain in the workwear (t-shirt etc.) worn while attending a fire incident (OR up to 3.6, 2.3-5.6), and indicate that cleaning at fire stations is not taken seriously (OR 2.4, 2.2-2.6). Firefighters personally viewing contamination as a "badge of honour" (BoH) were at least twice as likely to: remain in contaminated PPE after fire incidents (OR 2.3, 1.4-3.9), eat with sooty hands (OR 2.2, 1.9-2.5), notice soot in the nose/throat (OR 3.7, 2.7-5.2), and smell fire smoke on the body for more than a day after incidents (OR 2.0, 1.6-2.4). They were also more likely to indicate that cleaning at fire stations is not taken seriously (OR 2.5, 2.2-2.9) and that fire stations smell of smoke always/most of the time (OR 2.3, 2.0-2.6). Strong links were also found between belief in the BoH and never cleaning PPE (OR 1.9, 1.4-2.7), and eating while wearing contaminated PPE (OR 1.8, 1.5-2.2).

A new consensus on reconciling fire safety with environmental & health impacts of chemical flame retardants.

Flame retardants are chemical substances that are intended to mitigate fire safety risks posed by a range of goods including furniture, electronics, and building insulation. There are growing concerns about their effectiveness in ensuring fire safety and the potential harms they pose to human health and the environment. In response to these concerns, on 13 June 2022, a roundtable of experts was convened by the UKRI Six Clean Air Strategic Priorities Fund programme 7. The meeting produced a Consensus Statement that summarises the issues around the use of flame retardants, laying out a series of policy recommendations that should lead to more effective fire safety measures and reduce the human and environmental health risks posed by these potentially toxic chemicals.