Air pollution is a major cardiovascular risk factor, with particulate matter (PM) posing significant threats. The Po Valley remains among Europe’s most polluted areas. While PM₂.₅ is linked to cardiac dysfunction, its effects during pregnancy—especially under hypertensive conditions—are poorly defined. We investigated how prolonged PM exposure from Milan’s urban area affects cardiac electromechanical function in pregnant normotensive and hypertensive rats, and in a human embryonic stem cell-derived 3D cardiac spheroid. Pregnant normotensive and hypertensive (SHR) rats were exposed to saline solutions w/wo PM (2 mg/kg) three times weekly for 19 days. Cardiac spheroids were cultured in DMEM w/wo PM (10–50 µg/mL) for 8 days. We assessed cardiac function via in-vivo epicardial mapping and in-vitro optokinematic analysis. Inflammatory, toxicological, and molecular profiles were evaluated. Machine learning classified electrogram profiles in PM-exposed versus unexposed rats. In SHR rats, PM exposure increased rheobase (+ 39

Cancer accounts for nearly one in four deaths (22.8%) due to noncommunicable diseases globally. The urgency for new effective therapies is worsened by resistance. One strategy is to look for multimodal drugs, which undergo different pathways to achieve selective cytotoxicity. Thiosemicarbazones are known to act as antitumoral compounds through multiple modes of action, and Ni-(II) shares some coordination properties with Pt-(II) but is also accessible to redox reactions such as superoxide dismutation catalysis. We found that, in a list of four thiosemicarbazone Ni-(II) complexes all tested on various cancer cell lines, Ni4 displayed IC50 values down to 5 ± 2 μM and over 8-fold selectivity. We investigated how apoptosis was induced, finding at least two different simultaneous mechanisms both involving the Ni-(II) center: first, entrance of the nucleus and coordination of the minor groove of the DNA, modifying its helicity, and second, disruption of the reactive oxygen species (ROS) balance due to the stoichiometric interactions with radical species and catalytic dismutation of hydrogen peroxide, based on the aliphatic N4 substitution that induces a peculiar two-electron exchange reactivity on the Ni-(II) center. Even if we found that Ni2 (cytotoxic but nonselective) is as efficient as literature catalase-like mimics (k cat/K M: 10 ± 2 M-1·s-1), Ni4 treatment hits the upregulation of heme oxygenase (HO-1) and mitochondrial superoxide dismutase (SOD-2). Cyclic voltammetry was used to fully characterize both Ni complexes to investigate the mechanisms of the redox processes associated with electron transfer. Clarifying the cytotoxicity mechanisms, we found that the selectivity is related at least to albumin delivery. Albumin, highly concentrated in the mammalian serum, rapidly seizes the compounds and delivers them selectively to the cancer cells. We found that albumin forms a supramolecular complex with the whole coordination compounds, without sequestering the metal ion, and its affinity is highest for Ni4 (K b: 1.5 ± 0.9 × 106 M-1).

Impaired Ca2+ handling, and in particular leakage from the sarcoplasmic reticulum, is a critical mechanism in metabolic diseases affecting the heart. Phase-plane loop analysis provides an integrated assessment of excitation-contraction coupling (ECC) by capturing the dynamic relation between Ca2 + transients and mechanical contraction, exceeding standard time analysis limitations. Here, we investigated how mitochondrial encephalopathy, lactic acidosis and stroke-like episodes metabolic disorder (MELAS) impairs the ECC using cardiac spheroids from diseased human induced pluripotent stem cells (m3243A>G mutation) and matched control (mtDNA mutation <10%). High-speed dual-mode imaging at 200 fps enabled simultaneous acquisition of Ca2 + dynamics and spheroid kinematics. To uncover disease-specific mechanisms, supra-threshold electric field stimulation was applied to simulate increased energy demand. After signal extraction, we built our interpretation of phase-plane loops, comprising kinematic-calcium (Ki-Ca) loops, to quantify ECC efficiency. Time-domain analysis demonstrated that MELAS cardiac spheroids showed significant reduction in beat duration at kinematics (1.068 ± 0.066 s vs. 0.775 ± 0.094 s), as well as decreased Ca2+ transient duration (0.984 ± 0.049 s vs. 0.664 ± 0.042 s). Critically, Ki-Ca loop analysis provided a more complete picture where MELAS samples displayed visibly different loops and a significant reduction of their area compared to controls (0.129 ± 0.056 vs. 0.082 ± 0.163). These findings demonstrate that Ki-Ca loops provide a sensitive and integrative metric for detecting ECC dysfunction in human in vitro cardiac models. This approach offers mechanistic insight into how mitochondrial metabolic disorders, such as MELAS, compromise the coupling between Ca2 + cycling and contractility. KEY POINTS: Phase-plane Ki-Ca loops effectively contribute to understanding the excitation-contraction coupling (ECC) efficiency. Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes metabolic disorder (MELAS) impairs ECC in cardioid models. Cardiac challenge pacing protocol highlights beating anomaly in MELAS spheroids, uncovering ECC failure.

Photodynamic therapy (PDT) has been established as one of the most promising novel cancer therapies with fewer side-effects and enhanced efficacy compared to the currently available conventional treatments. However, its application has been hindered by the limitations that photosensitizers (PS) have. The combination of PS with metallic nanoparticles like platinum nanoparticles (PtNPs), can help to overcome these intrinsic drawbacks. In this work, the combination of PtNPs and the natural photosensitizer riboflavin (RF) is proposed. PtNPs are synthesized using RF (Pt@RF) as reducing and stabilizing agent in a one-step method, obtaining nanoparticles with mesoporous structure for UV triggered PDT. In view of possible future UV irradiation treatments, the degradation products of RF, ribitol (RB) and lumichrome (LC), this last being a photosensitizing byproduct, are also employed for the synthesis of porous PtNPs, obtaining Pt@LC and Pt@RB. When administered in vitro to lung cancer cells, all the samples elicit a strong decrease of cell viability and a decrease of intracellular ATP levels. The antitumoral effect of both Pt@RF and Pt@LC is triggered by UV-A irradiation. This antitumoral activity is caused by the induction of oxidative stress, shown in our study by the decrease in intracellular glutathione and increased expression of antioxidant enzymes.

The exploration of chemical space is crucial for advancing antibacterial drug discovery and developing novel therapeutic agents. We used a bismuth compound that restores carbapenem sensitivity in NDM-1-producing bacterial strains as a starting point to design a library of compounds through modifications of both the central metal core and ligand structure. The metal was substituted with other p-block metals like gallium(III) and antimony(III), while the ligand, a thiosemicarbazone, was derivatized, yielding a library of 16 compounds for biological evaluation. The synthesized compounds were tested for antimicrobial activity. Synergistic studies with resistant strains identified new lead compounds that restored antibiotic sensitivity. In vivo toxicity using Galleria mellonella larvae showed favorable safety profiles for several compounds. Despite strong in vitro activity, the compounds did not significantly improve survival rates in infected larvae, either as monotherapies or in combination with antibiotics. This study highlights the potential of rational lead compound modifications to identify novel antimicrobial agents.

Benzimidazole is a well-known pharmacophore present in 47 FDA-approved drugs and approximate to 100 experimental compounds. It shows promise for other applications, including antibacterial, antifungal, antiviral, and anticancer therapies. Many derivatives modulate oxidative stress by influencing reactive oxygen species (ROS), selectively inducing cancer cell death. Additionally, structural modificationsenhance antitumor activity and facilitate conjugation with metal centers. In this study, it is focused on the hybrid ligand 2-(1H-benzo[d]imidazol-2-yl)quinolin-8-ol (L) and its Cu(II) and Ni(II) complexes (1 and 2) as potential anticancer agents. These coordination systems are characterized, and their binding stability is assessed via UV-visible titrations and density functional theory (DFT) analysis, revealing that complex 2 is more stable than complex 1. It is then investigated how the ligand and the complexes can interact with ROS, with a view to a ROS-targeting cytotoxicity. These studies, supported by DFT, indicated that L and complex 1 are generally more interactive than complex 2. When tested on various cancer cell lines, it is found that L and complex 1 demonstrated modest to good efficacy. These results suggest that L is the primary active species, complex 1 acts as a prodrug, whereas the strong interaction with Ni(II) in 2 hinders the ligand's potential.

Nanoparticles toxicity is associated with cardiovascular diseases (CDs). Although epidemiological studies confirmed such link, they did not prove a direct causation on cardiac tissue. Normotensive and hypertensive (SHR) rats were exposed to titanium dioxide (TiO,) and diesel exhaust particles (DEP) from Euro3 and Euro4 derived-engines. We explored the interaction between NPs and in-vivo/in-vitro cardiac tissue and we determined the effect on electro-mechanical performance by evaluating genetic, morphological, functional and toxicological alterations. We observed a direct contamination of cardiac tissue by tracheallyinstilled NPs, correlated with structural remodeling, ROS, DNA damaged, modulation of ECGs and arrhythmogenesis. Such conditions are further aggravated in normotensive animal acutely exposed to Euro4-DEP and in SHR repeatedly exposed to 1i0,-NPs. Such NPs produce transient nanopores (≤50 nm), which causes membrane leakage and action potential reduction. Our proposed approaches show a direct involvement of NPs linked to CDs, by establishing a novel arrhythmogenic mechanism.

ROS (i.e., reactive oxygen species) scavenging is a key function of various Mn-based enzymes, including superoxide dismutases (SODs) and catalases, which are actively linked to oxidative stress-related diseases. In this study, we synthesized and characterized two novel Mn(III)-based synzymes (i.e., synthetic enzymes), designated C1 ([MnL1Cl(H2O)]Cl·3H2O) and C2 ([MnL2Cl2]·2H2O), which differ in the presence of a bridging aliphatic or aromatic group in the chelator. Using a range of analytical techniques, we found that the aromatic C2 bridge significantly influences the Mn(III) center’s cis-β configuration, unlike C1, which adopts a trans configuration. We then thoroughly evaluated the oxidation-reduction properties of C1 and C2, including their redox potentials (by cyclic voltammetry) and capacity to consume various ROS species (using DPPH, hydroxyl radical, hydrogen peroxide, and superoxide UV–visible spectrophotometric assays). The specific kinetics of the H2O2 dismutation process, as measured by a Clark-type electrode and time-resolved ESI-MS, revealed that both synzymes possess catalytic activity. Toxicological experiments using the Galleria mellonella larval model demonstrated the compounds’ innocuous nature towards higher eukaryotic organisms, while cytotoxicity assays confirmed their selective efficacy against lung cancer cells. Additional cytological assays, such as the thiobarbituric acid reactive substances assay and caspase-3 activity and p53 expression analysis, reported that C1 and C2 induce cytotoxicity against cancer cells via apoptosis rather than necrosis and behave very differently towards redox substances and ROS-regulating enzymes in vivo. These findings suggest that the structural differences between C1 and C2 lead to distinct redox properties and biological activities, highlighting the potential of these novel Mn(III)-based synzymes as therapeutic agents for the treatment of oxidative stress-related diseases, particularly lung cancer. Further studies are warranted to elucidate the underlying mechanisms of action and explore their clinical applications.

The aim of this work is to explore a new library of coordination compounds for medicinal applications. Gallium is known for its various applications in this field. Presently, indium is not particularly important in medicine, but it shares a lot of chemical traits with its above-mentioned lighter companion, gallium, and is also used in radio imaging. These metals are combined with thiosemicarbazones, ligating compounds increasingly known for their biological and pharmaceutical applications. In particular, the few ligands chosen to interact with these hard metal ions share the ideal affinity for a high charge density. Therefore, in this work we describe the synthesis and the characterization of the resulting coordination compounds. The yields of the reactions vary from a minimum of 21% to a maximum of 82%, using a fast and easy procedure. Nuclear Magnetic Resonance (NMR) and Infra Red (IR) spectroscopy, mass spectrometry, elemental analysis, and X-ray Diffraction (XRD) confirm the formation of stable compounds in all cases and a ligand-to-metal 2:1 stoichiometry with both cations. In addition, we further investigated their chemical and biological characteristics, via UV-visible titrations, stability tests, and cytotoxicity and antibiotic assays. The results confirm a strong stability in all explored conditions, which suggests that these compounds are more suitable for radio imaging applications rather than for antitumoral or antimicrobic ones.

Biochar is currently garnering interest as an alternative to commercial fertilizer and as a tool to counteract global warming. However, its use is increasingly drawing attention, particularly concerning the fine dust that can be developed during its manufacture, transport and use. This work aimed to assess the toxicity of fine particulate Biochar (<PM10) via in-vitro and in-vivo experiments as a first step for the evaluation of toxicity values. As in-vitro experiments, cell lines showed inhibition of proliferation following the reduction of expression genes involved in cell cycle control, increase in the production of ROS and IL-8, and decrease in intracellular ATP. In-vivo rat exposure induced hyperemia, edema, and inflammatory phenomena with infiltrations of neutrophil granulocytes and macrophages at the alveolar and bronchiolar levels. Both in-vitro and in-vivo studies highlighted how exposure to Biochar particulates leads to an inflammatory condition and oxidative stress.

Cancer continues to pose a global threat, underscoring the urgent need for more effective and safer treatment options. Gold-based compounds have recently emerged as promising candidates due to their diverse range of biological activities. In this study, three gold(III) complexes derived from thiosemicarbazone ligands have been synthesized, fully characterized, including their X-ray crystal structures. We conducted initial mode-of-action studies on DNA and BSA, followed by a comprehensive investigation into the cytotoxic effects of these novel gold(III) complexes on lung cancer cells (A549, H2052, and H28). The results demonstrated a concentration-dependent cytotoxic response, with H28 cells exhibiting the highest sensitivity to the treatment. Furthermore, the analysis of the cell cycle revealed that these compounds induce cell cycle arrest and promote apoptosis as a response to treatment. We also observed distinct morphological changes and increased oxidative stress, contributing significantly to cell death. Notably, these complexes exhibited the ability to suppress interleukin-6 production in mesothelioma cell lines, and this highlights their anti-inflammatory potential. To gain an initial understanding of cytotoxicity on healthy cells, hemolysis tests were conducted against human blood cells, with no evidence of hemolysis. Furthermore, a toxicity assessment through the in vivo Galleria mellonella model underscored the absence of detectable toxicity. These findings prove that these complexes are promising novel therapeutic agents for lung cancer.

The continuous rise of antimicrobial resistance is a serious threat to human health and already causing hundreds of thousands of deaths each year. While natural products and synthetic organic small molecules have provided the majority of our current antibiotic arsenal, they are falling short in providing new drugs with novel modes of action able to treat multidrug resistant bacteria. Metal complexes have recently shown promising results as antimicrobial agents, but the number of studied compounds is still vanishingly small, making it difficult to identify promising compound classes or elucidate structure-activity relationships. To accelerate the pace of discovery we have applied a combinatorial chemistry approach to the synthesis of metalloantibiotics. Utilizing robust Schiff-base chemistry and combining 7 picolinaldehydes with 10 aniline derivatives, and 5 axial ligands we have prepared a library of 420 novel manganese tricarbonyl complexes. All compounds were evaluated for their antibacterial properties and 10 lead compounds were identified, re-synthesized and fully characterized. All 10 compounds showed high and broad activity against Gram-positive bacteria. The best manganese complex displayed low toxicity against human cells with a therapeutic index of >100. In initial mode of action studies, we show that it targets the bacterial membrane without inducing pore formation or depolarisation. Instead, it releases its carbon monoxide ligands around the membrane and inhibits the bacterial respiratory chain. This work demonstrates that large numbers of metal complexes can be accessed through combinatorial synthesis and evaluated for their antibacterial potential, allowing for the rapid identification of promising metalloantibiotic lead compounds.

The toxicity of nanoparticles absorbed through contact or inhalation is one of the major concerns for public health. It is mandatory to continually evaluate the toxicity of nanomaterials. In vitro nanotoxicological studies are conventionally limited by the two dimensions. Although 3D bioprinting has been recently adopted for three-dimensional culture in the context of drug release and tissue regeneration, little is known regarding its use for nanotoxicology investigation. Therefore, aiming to simulate the exposure of lung cells to nanoparticles, we developed organoid-based scaffolds for long-term studies in immortalized cell lines. We printed the viscous cell-laden material via a customized 3D bioprinter and subsequently exposed the scaffold to either 40 nm latex-fluorescent or 11–14 nm silver nanoparticles. The number of cells significantly increased on the 14th day in the 3D environment, from 5 × 105 to 1.27 × 106, showing a 91% lipid peroxidation reduction over time and minimal cell death observed throughout 21 days. Administered fluorescent nanoparticles can diffuse throughout the 3D-printed scaffolds while this was not the case for the unprinted ones. A significant increment in cell viability from 3D vs. 2D cultures exposed to silver nanoparticles has been demonstrated. This shows toxicology responses that recapitulate in vivo experiments, such as inhaled silver nanoparticles. The results open a new perspective in 3D protocols for nanotoxicology investigation supporting 3Rs.

Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25–2000 μM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.

MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on human health is established and interest in them is progressively increasing. Environmental and occupational risk factors affecting human health include chemical agents. Benzene represents a pollutant of concern due to its ubiquity and because it may alter gene expression by epigenetic mechanisms, including miRNA expression changes. This review summarizes recent findings on miRNAs associated with benzene exposure considering in vivo, in vitro and human findings in order to better understand the molecular mechanisms through which benzene induces toxic effects and to evaluate whether selected miRNAs may be used as biomarkers associated with benzene exposure. Original research has been included and the study selection, data extraction and assessments agreed with PRISMA criteria. Both in vitro studies and human results showed a variation in miRNAs’ expression after exposure to benzene. In vivo surveys also exhibited this trend, but they cannot be regarded as conclusive because of their small number. However, this review confirms the potential role of miRNAs as “early warning” signals in the biological response induced by exposure to benzene. The importance of identifying miRNAs’ expression, which, once validated, might work as sentinel molecules to better understand the extent of the exposure to xenobiotics, is clear. The identification of miRNAs as a molecular signature associated with specific exposure would be advantageous for disease prevention and health promotion in the workplace.

Resistant bacteria represent an urgent worldwide threat. NDM-1-producing strains are rendering the last line antibiotics less effective. Six bismuth complexes of general formula BiLCl2, where L is a thiosemicarbazone bearing a quinoline moiety, have been synthesized and fully characterized, including their X-ray crystal structures. The synergistic relationship between the compounds and meropenem have been tested in a combination therapy in carbapenem-resistant Klebsiella pneumoniae (NTCT14331) carrying the NDM-1 gene. Quinoline-2-carboxaldehyde-N4-phenyl-3-thiosemicarbazone bismuth dichloride and carbapenem showed synergism in a dose dependent manner with negligible antibacterial activity when used in a monotherapy and could restore antibiotic sensitivity in the strain producing NDM-1 enzyme. The minimum inhibitory concentration (MIC) of meropenem lowered down 128 folds up to 2 μgmL-1, a concentration lower to the sensitivity level. The IC50 of the compound against A549 human lung carcinoma cells and HuDe human epithelial tissue was 46.96 ± 16.66 μM and 54.26 ± 9.89 μM respectively. The cytotoxicity against human cells was higher than the effective concentration needed for the synergistic effect in bacterial cells, indicating that a structural optimization of the compounds is needed.

Queer identities are often ignored in diversity initiatives, yet there is a growing body of research that describes notable heterosexist and gender-normative expectations in STEM that lead to unsupportive and discriminatory environments and to the lower persistence of queer individuals. Research on the experiences of queer-spectrum individuals is limited by current demographic practices. In surveys that are queer-inclusive there is no consensus on best practices, and individuals with queer genders and queer sexual, romantic, and related orientations are often lumped together in a general category (e.g. LGBTQ+). We developed two queer-inclusive demographics questions and administered them as part of a larger study in undergraduate engineering and computer science classes (n = 3698), to determine which of three survey types for gender (conventional, queered, open-ended) provided the most robust data and compared responses to national data to determine if students with queer genders and/or queer sexual, romantic, and related orientations were underrepresented in engineering and computer science programs. The gender survey with queer-identity options provided the most robust data, as measured by higher response rates and relatively high rates of disclosing queer identities. The conventional survey (male, female, other) had significantly fewer students disclose queer identities, and the open-ended survey had a significantly higher non-response rate. Allowing for multiple responses on the survey was important: 78% of those with queer gender identities and 9% of those with queer sexual, romantic and related orientations selected multiple identities within the same survey question. Queer students in our study were underrepresented relative to national data. Students who disclosed queer gender identities were 7/100ths of the expected number, and those with queer orientations were under-represented by one-quarter. Further work developing a research-based queered demographics instrument is needed for larger-scale changes in demographics practices, which will help others identify and address barriers that queer-spectrum individuals face in STEM.

Myocardial infarction causes 7.3 million deaths worldwide, mostly for fibrillation that electrically originates from the damaged areas of the left ventricle. Conventional cardiac bypass graft and percutaneous coronary interventions allow reperfusion of the downstream tissue but do not counteract the bioelectrical alteration originated from the infarct area. Genetic, cellular, and tissue engineering therapies are promising avenues but require days/months for permitting proper functional tissue regeneration. Here we engineered biocompatible silicon carbide semiconductive nanowires that synthetically couple, via membrane nanobridge formations, isolated beating cardiomyocytes over distance, restoring physiological cell-cell conductance, thereby permitting the synchronization of bioelectrical activity in otherwise uncoupled cells. Local in-situ multiple injections of nanowires in the left ventricular infarcted regions allow rapid reinstatement of impulse propagation across damaged areas and recover electrogram parameters and conduction velocity. Here we propose this nanomedical intervention as a strategy for reducing ventricular arrhythmia after acute myocardial infarction.

Some ten million cancer deaths occurred in 2020, highlighting the fact that the search for new anticancer drugs remains extremely topical. In the search for new coordination compounds with relevant biological properties, the choice of a metal ion is important for the design of the complex. In this regard, copper plays a peculiar role, thanks to its distinct properties. Thiosemicarbazones are, analogously, a unique class of ligands because they are easily modifiable, and therefore, extremely versatile in terms of modulating molecular properties. In this work, we synthesized and characterized, by means of X-ray diffraction, four new naphthaldehyde and anthraldehyde thiosemicarbazone derivatives and their copper complexes to be used in interaction studies with biological systems. The objective was to evaluate the antileukemic activity of these compounds. Reactions of these ligands with Cu(II) salts produced unexpected oxidation products and the isolation of Cu(I) metal complexes. One ligand and its related Cu(I) complex, which is stable in physiological conditions, were subjected to in vitro biological tests (UV-Vis and CD titration). An important interaction with DNA and an affinity toward BSA were observed in FT-IR experiments. Preliminary in vitro biological tests against a histiocytic lymphoma cell line revealed an interestingly low IC50 value, i.e., 5.46 µM, for the Cu(I) complex.