Low Intrinsic Toxicity Research Articles

P20-28 Toxicological effects caused by particles which exhibit no or very low intrinsic toxicity in inhalation toxicity studies: what are the challenges

P20-28 Toxicological effects caused by particles which exhibit no or very low intrinsic toxicity in inhalation toxicity studies: what are the challenges

Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways

Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP’s map road as well.

A comprehensive review of the anticancer effects of decursin.

Cancer is a globally complex disease with a plethora of genetic, physiological, metabolic, and environmental variations. With the increasing resistance to current anticancer drugs, efforts have been made to develop effective cancer treatments. Currently, natural products are considered promising cancer therapeutic agents due to their potent anticancer activity and low intrinsic toxicity. Decursin, a coumarin analog mainly derived from the roots of the medicinal plant Angelica sinensis, has a wide range of biological activities, including anti-inflammatory, antioxidant, neuroprotective, and especially anticancer activities. Existing studies indicate that decursin affects cell proliferation, apoptosis, autophagy, angiogenesis, and metastasis. It also indirectly affects the immune microenvironment and can act as a potential anticancer agent. Decursin can exert synergistic antitumor effects when used in combination with a number of common clinical anticancer drugs, enhancing chemotherapy sensitivity and reversing drug resistance in cancer cells, suggesting that decursin is a good drug combination. Second, decursin is also a promising lead compound, and compounds modifying its structure and formulation form also have good anticancer effects. In addition, decursin is not only a key ingredient in several natural herbs and dietary supplements but is also available through a biosynthetic pathway, with anticancer properties and a high degree of safety in cells, animals, and humans. Thus, it is evident that decursin is a promising natural compound, and its great potential for cancer prevention and treatment needs to be studied and explored in greater depth to support its move from the laboratory to the clinic.

Therapeutic potency of curcumin on radiodermatitis: A systematic review.

Radiodermatitis (RD) is a frequent adverse event of radiotherapy (RT). Currently, there is no consensus and approved protocol for the treatment of RD. Curcumin (CUR) is a natural polyphenol obtained from turmeric and it has low intrinsic toxicity in humans. The aim of this systematic review was to explore the efficacy of CUR for prevention and treatment of RD. A systematic literature review was performed in the following online databases: Cochrane library, PubMed, Scopus, Web of Science, MEDLINE, and EMBASE. Among the 5 selected records, 3 had a randomized clinical trial (RCT)-design and the other had a pilot and controlled study designed. The included studies were performed on breast cancer (N=3), head and neck cancers (N=1) and different types of cancer (N=1). Four of the studies reported that the application of curcumin in cancer patients undergoing radiotherapy is associated with decreased intensity of radiodermatitis. However, one study did not report any significant effect of CUR on radiodermatitis. This review provides substantial evidence which confirm the clinical value of CUR in cancer supportive care. Further prospective clinical trials in larger scales are warranted in order to determine the " supplemental form and dose of CUR" for RD prevention and treatment in patients receiving radiotherapy.

Capsaicin exerts synergistic pro-apoptotic effects with cisplatin in TSCC through the calpain pathway via TRPV1.

Capsaicin (CAP) exerts significant anti-tumor effects on a variety of tumors, with low intrinsic toxicity. Cisplatin (DDP) is currently the first-line drug for the treatment of oral cancer; however, its clinical efficacy is impeded by chemoresistance and negligible side effects. Whether the combined use of CAP and DDP has a synergistic antitumor effect on tongue squamous cell carcinoma (TSCC) cells and its underlying mechanisms remains unclear. The present study revealed that CAP reduced the activity of TSCC cells in a dose- and time-dependent manner. We also observed changes in the mitochondrial functional structure of TSCC cells, along with the induction of mitochondrial apoptosis. Moreover, when CAP was combined with DDP, a synergistic cytotoxic effect on TSCC cells was observed, which had a significant impact on inducing apoptosis, inhibiting proliferation, and disrupting the mitochondrial membrane potential in TSCC cells compared to the single-drug treatment and control groups. These effects are associated with TRPV1, a high-affinity CAP receptor. The combined use of CAP and DDP can activate the TRPV1 receptor, resulting in intracellular Ca2+ overload and activation of the calpain pathway, ultimately leading to mitochondrial apoptosis. This potential mechanism was validated in TSCC xenograft models. In conclusion, our findings clearly demonstrate that CAP exerts synergistic pro-apoptotic effects with DDP in TSCC through the calpain pathway mediated by TRPV1. Thus, CAP can be considered an effective adjuvant drug for DDP in the treatment of TSCC.

Oxidation potential of PM2.5 in a mechanical processing plant and its association with metal composition

Oxidative potential (OP) of particles is an emerging indicator of health that reflects their ability to induce oxidative stress and cause adverse health effects. It offers us a useful tool to evaluate the health effects of particles released by different industrial processes. We measured the OPv (volume normalized OP characterizes overall oxidative burden) and OPm (mass normalized OP characterizes intrinsic toxicity) of PM2.5 from a casting workshop, a machining workshop, a meeting room of a machining processing plant, and outdoors using dithiothreitol (DTT) assay. The observed variations were substantial and varied greatly, underscoring the diverse toxicological profiles of particulates from distinct sources. Overall, PM2.5 mass concentration and OPv were highest in the casting workshop (PM2.5: 669.26 ± 402.62 μg/m3, OPv: 69.55 ± 128.35 nmol/(min·m3)), followed by the machining workshop (PM2.5 = 85.51 ± 41.89 μg/m3, OPv = :5.38 ± 2.68 nmol/(min·m3)), outdoor (PM2.5: 30.77 ± 13.34 μg/m3, OPv: 1.83 ± 0.92 nmol/(min·m3)), and meeting room (PM2.5: 26.97 ± 12.03 μg/m3, OPv: 1.86 ± 1 nmol/(min·m3)). However, localized variances influenced by PM's intrinsic toxicity (OPm) reordered these rankings. For example, PM2.5 mass concentration at the spheroidizing/pouring zone in the casting workshop was the highest, but the OPv was not due to the low intrinsic toxicity of the particles. Spearman's correlation analysis implied that the OPv was significantly correlated with the concentration of transition metals Mn (ρ = 0.47, P < 0.01), Fe (ρ = 0.503, P < 0.01), and Zn (ρ = 0.507, P < 0.01) in addition to PM2.5 mass concentration (ρ = 0.879, P<0.01), and the OPm was significantly correlated with the mass fraction of Zn (ρ = 0.34, P < 0.05) and Al (ρ = 0.333, P < 0.05). Besides, environmental factors (wind speed, temperature relative humidity, CO2) did not contribute to the oxidation potential. Higher oxidation potential (OPv) means higher health risks, our findings underscore the imperative to consider both PM mass concentration and intrinsic toxicity for future air pollution control efforts.

Efficient Photoelectrochemical Hydrogen Generation Using Eco-Friendly "Giant" InP/ZnSe Core/Shell Quantum Dots.

InP quantum dots (QDs) are promising building blocks for use in solar technologies because of their low intrinsic toxicity, narrow bandgap, large absorption coefficient, and low-cost solution synthesis. However, the high surface trap density of InP QDs reduces their energy conversion efficiency and degrades their long-term stability. Encapsulating InP QDs into a wider bandgap shell is desirable to eliminate surface traps and improve optoelectronic properties. Here, we report the synthesis of "giant" InP/ZnSe core/shell QDs with tunable ZnSe shell thickness to investigate the effect of the shell thickness on the optoelectronic properties and the photoelectrochemical (PEC) performance for hydrogen generation. The optical results demonstrate that ZnSe shell growth (0.9-2.8 nm) facilitates the delocalization of electrons and holes into the shell region. The ZnSe shell simultaneously acts as a passivation layer to protect the surface of InP QDs and as a spatial tunneling barrier to extract photoexcited electrons and holes. Thus, engineering the ZnSe shell thickness is crucial for the photoexcited electrons and hole transfer dynamics to tune the optoelectronic properties of "giant" InP/ZnSe core/shell QDs. We obtained an outstanding photocurrent density of 6.2 mA cm-1 for an optimal ZnSe shell thickness of 1.6 nm, which is 288% higher than the values achieved from bare InP QD-based PEC cells. Understanding the effect of shell thickness on surface passivation and carrier dynamics offers fundamental insights into the suitable design and realization of eco-friendly InP-based "giant" core/shell QDs toward improving device performance.

Exposure to cis- and trans-regioisomers of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-glutathione result in quantitatively and qualitatively different cellular effects in RPTEC/TERT1 cells

Bioactivation of trichloroethylene (TCE) via glutathione conjugation is associated with several adverse effects in the kidney and other extrahepatic tissues. Of the three regioisomeric conjugates formed, S-(1,2-trans-dichlorovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione and S-(2,2-dichlorovinyl)-glutathione, only 1,2-trans-DCVG and its corresponding cysteine-conjugate, 1,2-trans-DCVC, have been subject to extensive mechanistic studies. In the present study, the metabolism and cellular effects of 1,2-cis-DCVG, the major regioisomer formed by rat liver fractions, and 1,2-cis-DCVC were investigated for the first time using RPTEC/TERT1-cells as in vitro renal model. In contrast to 1,2-trans-DCVG/C, the cis-regioisomers showed minimal effects on cell viability and mitochondrial respiration. Transcriptomics analysis showed that both 1,2-cis-DCVC and 1,2-trans-DCVC caused Nrf2-mediated antioxidant responses, with 3 µM as lowest effective concentration. An ATF4-mediated integrated stress response and p53-mediated responses were observed starting from 30 µM for 1,2-trans-DCVC and 125 µM for 1,2-cis-DCVC. Comparison of the metabolism of the DCVG regioisomers by LC/MS showed comparable rates of processing to their corresponding DCVC. No detectable N-acetylation was observed in RPTEC/TERT1 cells. Instead, N-glutamylation of DCVC to form N-γ-glutamyl-S-(dichlorovinyl)-L-cysteine was identified as a novel route of metabolism. The results suggest that 1,2-cis-DCVC may be of less toxicological concern for humans than 1,2-trans-DCVC, considering its lower intrinsic toxicity and lower rate of formation by human liver fractions.

Modified Mycotoxins, a Still Unresolved Issue

Mycotoxins are toxic secondary metabolites produced by filamentous microfungi on almost every agricultural commodity worldwide. After the infection of crop plants, mycotoxins are modified by plant enzymes or other fungi and often conjugated to more polar substances, like sugars. The formed—often less toxic—metabolites are stored in the vacuole in soluble form or bound to macromolecules. As these substances are usually not detected during routine analysis and no maximum limits are in force, they are called modified mycotoxins. While, in most cases, modified mycotoxins have lower intrinsic toxicity, they might be reactivated during mammalian metabolism. In particular, the polar group might be cleaved off (e.g., by intestinal bacteria), releasing the native mycotoxin. This review aims to provide an overview of the critical issues related to modified mycotoxins. The main conclusion is that analytical aspects, toxicological evaluation, and exposure assessment merit more investigation.

Bioanalytical Applications of Graphene Quantum Dots for Circulating Cell-Free Nucleic Acids: A Review.

Graphene quantum dots (GQDs) are carbonaceous nanodots that are natural crystalline semiconductors and range from 1 to 20 nm. The broad range of applications for GQDs is based on their unique physical and chemical properties. Compared to inorganic quantum dots, GQDs possess numerous advantages, including formidable biocompatibility, low intrinsic toxicity, excellent dispensability, hydrophilicity, and surface grating, thus making them promising materials for nanophotonic applications. Owing to their unique photonic compliant properties, such as superb solubility, robust chemical inertness, large specific surface area, superabundant surface conjugation sites, superior photostability, resistance to photobleaching, and nonblinking, GQDs have emerged as a novel class of probes for the detection of biomolecules and study of their molecular interactions. Here, we present a brief overview of GQDs, their advantages over quantum dots (QDs), various synthesis procedures, and different surface conjugation chemistries for detecting cell-free circulating nucleic acids (CNAs). With the prominent rise of liquid biopsy-based approaches for real-time detection of CNAs, GQDs-based strategies might be a step toward early diagnosis, prognosis, treatment monitoring, and outcome prediction of various non-communicable diseases, including cancers.

The use of sewage sludge as remediation for imidacloprid toxicity in soils.

This study investigated the influence of the sewage sludge (SS) soil amendment on the chronic toxicity of imidacloprid (through the seed dressing formulation MUCH 600 FS®-600g active ingredient L-1) to collembolans Folsomia candida. Individuals 10-12days old were exposed to two contrasting tropical soils (Oxisol and Entisol) amended with SS doses (0, 20, 40, 80, 160, and 320g SS kg-1 soil; the SS doses have low intrinsic toxicity, which was checked before its application) in a full factorial combination with five imidacloprid concentrations (varying from 0.25 to 4mgkg-1 in Oxisol and 0.03-0.5mgkg-1 in Entisol) plus a control. None of the SS doses (without imidacloprid) in both soils reduced the number of generated juvenile collembolans. The imidacloprid concentrations reducing the collembolan reproduction in 50% (EC50) in Oxisol and Entisol without SS were 0.49 and 0.08mgkg-1, respectively. However, the EC50 values generally increased with increasing SS doses in soils, varying from 1.03 to 1.41 in Oxisol and 0.07 to 0.21 in Entisol. The SS-amended soils showed 2.1- to 2.9-fold lower imidacloprid toxicity (EC50-based) in Oxisol and 1.8- to 2.7-fold lower toxicity in Entisol. Our results suggest the most effective SS doses alleviating the imidacloprid toxicity (EC50-based) to collembolans are 20gkg-1 in Oxisol and 80gkg-1 in Entisol. These results indicate that the tested SS has the potential to be employed as a soil amendment agent by reducing the toxicity of imidacloprid to the reproduction of F. candida.

Polyglycerol Functionalized 10 B Enriched Boron Carbide Nanoparticle as an Effective Bimodal Anticancer Nanosensitizer for Boron Neutron Capture and Photothermal Therapies.

Boron neutron capture therapy (BNCT) is a non-invasive cancer treatment with little adverse effect utilizing nuclear fission of 10 B upon neutron irradiation. While neutron source has been developed from a nuclear reactor to a compact accelerator, only two kinds of drugs, boronophenylalanine and sodium borocaptate, have been clinically used for decades despite their low tumor specificity and/or retentivity. To overcome these challenges, various boron-containing nanomaterials, or "nanosensitizers", have been designed based on micelles, (bio)polymers and inorganic nanoparticles. Among them, inorganic nanoparticles such as boron carbide can include a much higher 10 B content, but successful in vivo applications are very limited. Additionally, recent reports on the photothermal effect of boron carbide are motivating for the addition of another modality of photothermal therapy. In this study, 10 B enriched boron carbide (10 B4 C) nanoparticle is functionalized with polyglycerol (PG), giving 10 B4 C-PG with enough dispersibility in a physiological environment. Pharmacokinetic experiments show that 10 B4 C-PG fulfills the following three requirements for BNCT; 1) low intrinsic toxicity, 2) 10 B in tumor/tumor tissue (wt/wt) ≥ 20ppm, and 3) 10 B concentrations in tumor/blood ≥ 3. In vivo study reveals that neutron irradiation after intravenous administration of 10 B4 C-PG suppresses cancer growth significantly and eradicates cancer with the help of near-infrared light irradiation.

A Boron Delivery Antibody (BDA) with Boronated Specific Residues: New Perspectives in Boron Neutron Capture Therapy from an In Silico Investigation.

Boron Neutron Capture Therapy (BNCT) is a tumor cell-selective radiotherapy based on a nuclear reaction that occurs when the isotope boron-10 (10B) is radiated by low-energy thermal neutrons or epithermal neutrons, triggering a nuclear fission response and enabling a selective administration of irradiation to cells. Hence, we need to create novel delivery agents containing 10B with high tumor selectivity, but also exhibiting low intrinsic toxicity, fast clearance from normal tissue and blood, and no pharmaceutical effects. In the past, boronated monoclonal antibodies have been proposed using large boron-containing molecules or dendrimers, but with no investigations in relation to maintaining antibody specificity and structural and functional features. This work aims at improving the potential of monoclonal antibodies applied to BNCT therapy, identifying in silico the best native residues suitable to be substituted with a boronated one, carefully evaluating the effect of boronation on the 3D structure of the monoclonal antibody and on its binding affinity. A boronated monoclonal antibody was thus generated for specific 10B delivery. In this context, we have developed a case study of Boron Delivery Antibody Identification Pipeline, which has been tested on cetuximab. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer.

Spider Toxin Peptide-Induced NIR Gold Nanocluster Fabrication for GSH-Responsive Cancer Cell Imaging and Nuclei Translocation.

Goldnanoclusters (GNCs) have become a promising nanomaterial for bioimaging because of their unique optical properties and biocompatibility. In this study, lycosin-I peptide, which possesses a highly selective anticancer activity by affecting the permeability of cancer cell membrane, was firstly modified for constructing fluorescent GNCs (LGNCs) for bioimaging of tumor cells. The obtained LGNCs exhibited strong near-infrared (NIR) fluorescence, which can be further enhanced by the peptide-induced aggregation and selectively stained three cancerous cell lines over normal cell lines with low intrinsic toxicity. After uptake by tumor cells, LGNC aggregates can be depolymerized into ultrasmall nanoclusters by high-level glutathione (GSH) and realize the nuclear targeting translocation. Collectively, our work suggests the potential of natural active biomolecules in designing NIR fluorescent GNCs for bioimaging.

A toxicogenomics approach reveals characteristics supporting the honey bee (Apis mellifera L.) safety profile of the butenolide insecticide flupyradifurone

Flupyradifurone, a novel butenolide insecticide, selectively targets insect nicotinic acetylcholine receptors (nAChRs), comparable to structurally different insecticidal chemotypes such as neonicotinoids and sulfoximines. However, flupyradifurone was shown in acute toxicity tests to be several orders of magnitude less toxic to western honey bee (Apis mellifera L.) than many other insecticides targeting insect nAChRs. The underlying reasons for this difference in toxicity remains unknown and were investigated here. Pharmacokinetic studies after contact application of [14C]flupyradifurone to honey bees revealed slow uptake, with internalized compound degraded into a few metabolites that are all practically non-toxic to honey bees in both oral and contact bioassays. Furthermore, receptor binding studies revealed a lack of high-affinity binding of these metabolites to honey bee nAChRs. Screening of a library of 27 heterologously expressed honey bee cytochrome P450 enzymes (P450s) identified three P450s involved in the detoxification of flupyradifurone: CYP6AQ1, CYP9Q2 and CYP9Q3. Transgenic Drosophila lines ectopically expressing CYP9Q2 and CYP9Q3 were significantly less susceptible to flupyradifurone when compared to control flies, confirming the importance of these P450s for flupyradifurone metabolism in honey bees. Biochemical assays using the fluorescent probe substrate 7-benzyloxymethoxy-4-(trifluoromethyl)-coumarin (BOMFC) indicated a weak, non-competitive inhibition of BOMFC metabolism by flupyradifurone. In contrast, the azole fungicides prochloraz and propiconazole were strong nanomolar inhibitors of these flupyradifurone metabolizing P450s, explaining their highly synergistic effects in combination with flupyradifurone as demonstrated in acute laboratory contact toxicity tests of adult bees. Interestingly, the azole fungicide prothioconazole is only slightly synergistic in combination with flupyradifurone – an observation supported by molecular P450 inhibition assays. Such molecular assays have value in the prediction of potential risks posed to bees by flupyradifurone mixture partners under applied conditions. Quantitative PCR confirmed the expression of the identified P450 genes in all honey bee life-stages, with highest expression levels observed in late larvae and adults, suggesting honey bees have the capacity to metabolize flupyradifurone across all life-stages. These findings provide a biochemical explanation for the low intrinsic toxicity of flupyradifurone to honey bees and offer a new, more holistic approach to support bee pollinator risk assessment by molecular means.

Apigenin Inhibits the Growth of Hepatocellular Carcinoma Cells by Affecting the Expression of microRNA Transcriptome

BackgroundApigenin, as a natural flavonoid, has low intrinsic toxicity and has potential pharmacological effects against hepatocellular carcinoma (HCC). However, the molecular mechanisms involving microRNAs (miRNAs) and their target genes regulated by apigenin in the treatment of HCC have not been addressed.ObjectiveIn this study, the molecular mechanisms of apigenin involved in the prevention and treatment of HCC were explored in vivo and in vitro using miRNA transcriptomic sequencing to determine the basis for the clinical applications of apigenin in the treatment of HCC.MethodsThe effects of apigenin on the proliferation, cell cycle progression, apoptosis, and invasion of human hepatoma cell line Huh7 and Hep3B were studied in vitro, and the effects on the tumorigenicity of Huh7 cells were assessed in vivo. Then, a differential expression analysis of miRNAs regulated by apigenin in Huh7 cells was performed using next-generation RNA sequencing and further validated by qRT-PCR. The potential genes targeted by the differentially expressed miRNAs were identified using a curated miRTarBase miRNA database and their molecular functions were predicted using Gene Ontology and KEGG signaling pathway analysis.ResultsCompared with the control treatment group, apigenin significantly inhibited Huh7 cell proliferation, cell cycle, colony formation, and cell invasion in a concentration-dependent manner. Moreover, apigenin reduced tumor growth, promoted tumor cell necrosis, reduced the expression of Ki67, and increased the expression of Bax and Bcl-2 in the xenograft tumors of Huh7 cells. Bioinformatics analysis of the miRNA transcriptome showed that hsa-miR-24, hsa-miR-6769b-3p, hsa-miR-6836-3p, hsa-miR-199a-3p, hsa-miR-663a, hsa-miR-4739, hsa-miR-6892-3p, hsa-miR-7107-5p, hsa-miR-1273g-3p, hsa-miR-1343, and hsa-miR-6089 were the most significantly up-regulated miRNAs, and their key gene targets were MAPK1, PIK3CD, HRAS, CCND1, CDKN1A, E2F2, etc. The core regulatory pathways of the up-regulated miRNAs were associated with the hepatocellular carcinoma pathway. The down-regulated miRNAs were hsa-miR-181a-5p and hsa-miR-148a-3p, and the key target genes were MAPK1, HRAS, STAT3, FOS, BCL2, SMAD2, PPP3CA, IFNG, MET, and VAV2, with the core regulatory pathways identified as proteoglycans in cancer pathway.ConclusionApigenin can inhibit the growth of HCC cells, which may be mediated by up-regulation or down-regulation of miRNA molecules and their related target genes.

Polyamidoamine-based nanovector for the efficient delivery of methotrexate to U87 glioma cells.

The purpose of this study was to design a polyamidoamine (PAMAM)-based nanovector for the efficient delivery of methotrexate to U87 glioma cells. To this end, 0-100% acetylated PAMAM dendrimers of the fourth generation were synthesized and evaluated using drug encapsulation measurements, molecular dynamics simulations, neurotoxicity assays and neuronal internalization experiments. The best system was tested as a nanovector for methotrexate delivery to U87 glioma cells. The authors found that 25% acetylated PAMAM dendrimers of the fourth-generation combine low intrinsic toxicity, large drug complexation capacity and efficient internalization into hippocampal neurons. Nanovector complexation enhances the cytotoxic response of methotrexate against U87 glioma cells compared with free drug solutions. In conclusion, 25% acetylated PAMAM dendrimers of the fourth-generation increase drug uptake by glioma cells and thereby act as efficient nanovectors for methotrexate delivery.

Site-Specific Antibody-Drug Conjugates in Triple Variable Domain Fab Format.

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic toxicity. For example, in the therapy of solid malignancies, the limited tumor tissue penetration and distribution of ADCs in IgG format mitigates a uniform distribution of the cytotoxic payload. Here, we report triple variable domain Fab (TVD–Fab) as a new format that affords the site-specific and stable generation of monovalent ADCs without the Fc domain and a drug-to-antibody ratio (DAR) of 2. TVD–Fabs harbor three variable fragment (Fv) domains: one for tumor targeting and two for the fast, efficient, precise, and stable conjugation of two cargos via uniquely reactive lysine residues. The biochemical and in vitro cytotoxicity properties of a HER2-targeting TVD–Fab before and after conjugation to a tubulin inhibitor were validated. In vivo, the TVD–Fab antibody carrier revealed a circulatory half-life of 13.3 ± 2.5 h and deeper tumor tissue distribution compared to our previously reported dual variable domain (DVD)–IgG1 format. Taken together, the TVD–Fab format merits further investigations as an antibody carrier of site-specific ADCs targeting solid malignancies.

Physicochemical alterations and toxicity of InP alloyed quantum dots aged in environmental conditions: A safer by design evaluation

Due to their unique optical properties, quantum dots (QDs) are used in a number of optoelectronic devices and are forecasted to be used in the near future for biomedical applications. The most popular QD composition consists of cadmium selenide (CdSe) or cadmium telluride (CdTe), which has been shown to pose health risks due to the release of toxic cadmium (Cd) ions. Due to similar optical properties but lower intrinsic toxicity, indium phosphide (InP) QDs have been proposed as a safer alternative. Nevertheless, investigations regarding their safety and possible toxicological effects are still in their infancy.The fate and toxicity of seven different water-dispersible indium (In)-based QDs, either pristine or after ageing in a climatic chamber, was evaluated. The core of these QDs was composed of indium, zinc and phosphorus (InZnP) or indium, zinc, phosphorus and sulfur (InZnPS). They were assessed either as core-only or as core-shell QDs, for which the core was capped with a shell of zinc, selenium and sulfur (Zn(Se,S)). Their surface was functionalized using either penicillamine or glutathione.In their pristine form, these QDs showed essentially no cytotoxicity. The particular case of InZnPS QD showed that core-shell QDs were less cytotoxic than core-only QDs. Moreover, surface functionalization with either penicillamine or glutathione did not appreciably influence cytotoxicity but affected QD stability. These QDs did not lead to over-accumulation of reactive oxygen species in exposed cells, or to any oxidative damage to cellular DNA. However, accelerated weathering in a climatic chamber led to QD precipitation and degradation, together with significant cytotoxic effects. Ageing led to dissociation of InP and ZnS bonds, and to complexation of In and Zn ions with carboxylate and/or phosphate moieties.These results show that InZnP and InZnPS alloyed QDs are safer alternatives to CdSe QDs. They underline the necessity to preserve as much as possible the structural integrity of QDs, for instance by developing more robust shells, in order to ensure their safety for future applications.

What is the impact of surface modifications and particle size on commercial titanium dioxide particle samples? – A review of in vivo pulmonary and oral toxicity studies – Revised 11-6-2018

There is an ongoing discussion on the influence of surface-modifications on the toxicity of commercial particulate materials and how alterations in physical-chemical properties of surfaces impact toxicity. Titanium dioxide (TiO2) is a poorly soluble particulate material of significant socioeconomic importance that largely exists as surface-modified particle-types in commerce. The observed toxicological effects of TiO2 are primarily due to particle effects rather than substance chemistry, as such TiO2 is commonly considered to be a poorly soluble low toxicity (PSLT) particle. This review provides an overview of the effect of surface modifications on the pulmonary and oral toxicity of commercial TiO2 particles with emphasis on in vivo studies with appropriate controls, and where both surface modified and untreated materials are present in the same study. Published literature findings involving pulmonary and oral exposures to surface modified TiO2 particles were reviewed and evaluated for quality and commercial relevance. Suitable publications involving animal studies were identified and summarized. Several studies were identified that have evaluated commercially-relevant surface-modified forms of titanium dioxide with appropriate data quality and with direct comparison to untreated counterparts. Hydrophilic inorganic surface modifications including silica, alumina/alumina hydroxide depositions have been tested along with common hydrophilic and hydrophobic-organic surface treatments. The results for both pigmentary and nanoscale materials demonstrate similar behaviour and indicate limited impact of particle size, surface chemistry, surface charge and surface wettability on observed pulmonary or oral toxicity effects. The low intrinsic toxicity of the TiO2 base particle and evaluated surface modifications may account for the observed outcomes. A few published studies have drawn different conclusions; however, these were either not conducted using commercial TiO2 samples (with surface coatings), had several confounding variables to investigate, or were carried out using mouse strains. The differences in experimental designs are described. The identified pulmonary and oral toxicity studies largely indicate that surface modifications and particle size alone have little or no impact on the lung toxicity of TiO2 particles, following pulmonary exposures when all constituent materials are comprised of chemicals of low specific toxicity particles. In addition, based upon the results of 2 oral toxicity studies, one with surface treated TiO2 particles (OECD 408) and one without surface treated (OECD 407) TiO2 particles, there appears to have been no adverse impact on toxicity with the surface-coated material, as both studies produced no adverse effects at the very high doses tested.