Toxic Responses Research Articles

Lake water chemistry and local adaptation shape NaCl toxicity in Daphnia ambigua.

The increasing application of road deicing agents (e.g., NaCl) has caused widespread salinization of freshwater environments. Chronic exposure to toxic NaCl levels can impact freshwater biota at genome to ecosystem scales, yet the degree of harm caused by road salt pollution is likely to vary among habitats and populations. The background ion chemistry of freshwater environments may strongly impact NaCl toxicity, with greater harm occurring in ion-poor, soft water conditions. In addition, populations exposed to salinization may evolve increased NaCl tolerance. Notably, if organisms are adapted to the water chemistry of their natal environment, toxicity responses may also vary among populations in a given test medium. We examined the potential for this evolutionary and environmental context to interact in shaping NaCl toxicity with a pair of laboratory reciprocal transplant toxicity experiments, using natural populations of the water flea Daphnia ambigua collected from three lakes that vary in ion availability and composition. We observed a strong effect of the lake water environment on NaCl toxicity in both trials. NaCl caused a much greater decline in reproduction and r in lake water from a low-ion/calcium-poor environment (20 μS/cm specific conductance; 1.7 mg/L Ca2+) compared with water from both a Ca2+-rich lake (55 μS/cm; 7.2 mg/L Ca2+) and an ion-rich coastal lake (420 μS/cm; 3.4 mg/L Ca2+). Daphnia from this coastal lake were most robust to the effects of NaCl on reproduction and r. A significant interaction between the population and lake water environment shaped survival in both trials, suggesting that local adaptation to the test waters used may have contributed to toxicity responses. Our findings that the lake water environment, adaptation to that environment, and adaptation to a contaminant of interest may shape toxicity demonstrate the importance of considering environmental and biological complexity in mitigating pollution impacts.

Zinc toxicity and tolerance-related responses in Inga marginata and Allophylus edulis seedlings

Although zinc (Zn) is a micronutrient, excessive amounts in the soil can have toxic effects on plants. Fertilizers, limestone materials, pesticides, and fungicides added with Zn have contributed to increasing the concentration of this element in agricultural soils. Accordingly, it is necessary to find Zn-tolerant plant species to be properly used in degraded soil restoration programs. Thus, the current study aims to investigate the influence of different Zn concentrations on photosynthetic variables, antioxidant activity, and growth of I. marginata and A. edulisseedlings to determine their potential to be used as phytoremediation species. The experiment was installed in a 2×5 factorial scheme, with the first factor being two species (Allophylus edulis and Inga marginata), and the second factor: five concentrations of Zn (2, 75, 150, 225, and 300 μM), with three replications per treatment. Each sampling unit consisted of a pot with five plants. Photosynthetic, morphological variables of the shoot and root systems, chlorophyll a fluorescence, photosynthetic pigments, antioxidant enzyme activity, lipid peroxidation, hydrogen peroxide concentration, and Zn accumulated in the roots and shoot were evaluated. Zn stress has activated an efficient antioxidant system, which reduced oxidative damage in the leaves of both species; consequently, it did not decrease shoot biomass production in Inga marginata and Allophylus edulis seedlings. High Zn accumulation in plant tissues and lack of negative effects on Inga marginata and Allophylus edulis shoot have suggested that these plant species are tolerant to Zn and may be indicated for Zn-polluted soil phytoremediation purposes.

Healthy aging: when periodontal health matters

Providing care for the elderly has been considered a significant challenge for modern medicine. As age progresses, diseases become more frequent and severe than those observed at a younger age. This is particularly relevant for infectious diseases, typical in the elderly and usually associated with poor outcomes. Moreover, when persisting and diffusing into the bloodstream (i.e. bacteremia), these infections keep up with the demand for immune cells’ response and consequently increase the concentration of inflammatory markers systemically. This phenomenon is known as “inflammaging”, which potentially triggers or facilitates the development and progression of several age-related disorders, such as cancer, cardiovascular and neurodegenerative diseases. Periodontal disease is one of the most prominent among the disparate number of causal factors responsible for bacteremia and low-grade systemic inflammation in the aging population. This inflammatory disorder is triggered by a dysbiosis of certain bacterial species that activates a massive local toxic deleterious immune response leading to non-reversible damage of supportive tissues surrounding the teeth. In chronic, oral pathogens and their toxic factors can penetrate the bloodstream contributing to systemic inflammation. Based on this premise, it seems evident that maintaining oral health in the elderly is vital not just for owning healthy mouth but also because it contributes to a healthy aging. This review provides an updated account of molecular insights into the bidirectional association between oral health and “successful” aging.

Differential effects of benzo[a]pyrene exposure on glutathione and purine metabolism in keratinocytes: Dose-dependent and UV co-exposure effects.

Polycyclic aromatic hydrocarbons with the key substance benzo[a]pyrene (B[a]P) are widespread pollutants in the environment and at working places. Nonetheless, the exact underlying mechanisms of toxicological effects caused by B[a]P especially in absence and presence of UV irradiation remain uncertain. This study examines variations in exposure conditions: low B[a]P (4 nM), low B[a]P + UV and high B[a]P (4 μM), selected based on pertinent cytotoxicity assessments. Following cell viability evaluations post-treatment with varied B[a]P concentrations and UV irradiation, the identified concentrations underwent detailed metabolomic analysis via gas chromatography-mass spectrometry. Subsequently, resulting changes in metabolic profiles across these distinct exposure groups are comprehensively compared. Chemometric analyses showed modest regulation of metabolites after low B[a]P exposure compared to control conditions. High B[a]P and low B[a]P + UV exposure significantly increased regulation of metabolic pathways, indicating that additional UV irradiation plus low B[a]P is as demanding for the cells as higher B[a]P treatment alone. Further analysis revealed exposure-dependent regulation of glutathione-important for oxidative defence-and purine metabolism-important for DNA base synthesis. Only after low B[a]P, oxidative defence appeared to be able to compensate for B[a]P-induced perturbations of the oxidative homeostasis. In contrast, purine metabolism already responded towards adversity at low B[a]P. The metabolomic results give an insight into the mechanisms leading to the toxic response and confirm the strong effects of co-exposure on oxidative defence and DNA repair in the model studied.

Residual hydrocarbons in long-term contaminated soils: implications to risk-based management

Petroleum hydrocarbon (PHC) contamination is a widespread and severe environmental issue affecting many countries’ resource sectors. PHCs are mixtures of hydrocarbon compounds with varying molar masses that naturally attenuate at different rates. Lighter fractions attenuate first, followed by medium-molar-mass constituents, while larger molecules remain for longer periods. This results in significant regulatory challenges concerning residual hydrocarbons in long-term contaminated soils. This study examined the potential risks associated with residual PHC and its implications for risk-based management of heavily contaminated soils (23,000–26,000 mg PHC/kg). Ecotoxicological properties, such as seedling emergence and growth of two native plant species—small Flinders grass (Iseilema membranaceum) and ruby saltbush (Enchylaena tomentosa)—and earthworm survival tests in PHC-contaminated soils, were assessed. Additionally, the effects of aging on the attenuation of PHC in contaminated soils were evaluated. Toxicity responses of plant growth parameters were determined as no-observed-effect concentrations: 75%–100% for seedling emergence, < 25%–75% for plant shoot height, and 75%–100% for earthworm survival. After 42 weeks of aging, the total PHC levels in weathered soils decreased by 14% to 30% and by 67% in diesel-spiked soil due to natural attenuation. Dehydrogenase enzyme activity in soils increased during the initial aging period. Furthermore, a clear shift of bacterial communities was observed in the soils following aging, including enrichment of PHC-resistant and -utilizing bacteria—for example, Nocardia sp. This study underscores the potential of natural attenuation for eco-friendly and cost-effective soil management, underlining that its success depends on site-specific factors like water content and nutrient availability. Therefore, we recommend detailed soil assessments to evaluate these conditions prior to adopting a risk-based management approach.

Sediment Quality Indices for the Assessment of Heavy Metal Risk in Nador Lagoon Sediments (Morocco) Using Multistatistical Approaches

Heavy metals in coastal ecosystems caused by the increased expansion of urbanization, industrialization, and agricultural practices have become a significant environmental risk to human well-being. This study evaluates and compares 17 sediment quality indices to examine the possible ecological and human health risks associated with heavy metal concentrations in the sediments of the Nador lagoon in Morocco. The concentration order of the HMs and sulfurs evaluated was S &gt; Sr &gt; Ba &gt; V &gt; Zr &gt; Zn &gt; Cr &gt; Rb &gt; La &gt; Cu &gt; Pb &gt; Ni &gt; Ce &gt; Nd &gt; Co &gt; Sc &gt; Nb &gt; Ga &gt; Th &gt; Y &gt; Hf. Sulfurs, Pb, Sr, and Nd exhibited concentrations that exceeded geochemical background values. The analysis of the sediment quality indices allowed us to understand that the Nador lagoon was moderately to strongly polluted by heavy metals originating from various anthropogenic activities. Results from the Sediment Quality Guidelines indicated a toxic response in the benthic organisms within the lagoon, while the ecological hazard analysis revealed a very high risk of heavy metal contamination in the ecosystem. The Hazard Index for non-carcinogenic values was below the limit, suggesting a lack of non-cancerous effects. However, Cu and Pb concentrations surpassed the Lifetime Cancer Risk range, indicating a potential cancer risk with prolonged exposure. Integrating our research into coastal management frameworks can contribute to the preservation and enhancement of these coastal ecosystems for future generations.

Arsenic and chromium induced hepatotoxicity in zebrafish (Danio rerio) at environmentally relevant concentrations: Mixture effects and involvement of Nrf2-Keap1-ARE pathway

Arsenic (As) and chromium (Cr), two well-known cytotoxic and carcinogenic metals are reported to coexist in industrial effluents and groundwater. Their individual toxicities have been thoroughly studied but the combined effects, especially the mechanism of toxicity and cellular stress response remain unclear. Considering co-exposure as a more realistic scenario, current study compared the individual and mixture effects of As and Cr in the liver of zebrafish (Danio rerio). Fish were exposed to environmentally relevant concentrations of As and Cr for 15, 30 and 60 days. ROS generation, biochemical stress parameters like lipid peroxidation, reduced glutathione content, catalase activity and histological alterations were studied. Results showed increase in ROS production, MDA content and GSH level; and vicissitude in catalase activity as well as altered histoarchitecture, indicating oxidative stress conditions after individual and combined exposure of As and Cr which were additive in nature. This study also included the expression of Nrf2, the key regulator of antioxidant stress responses and its nuclear translocation. Related antioxidant and xenobiotic metabolizing enzyme genes like keap1, nqo1, ho1, mnsod and cyp1a were also studied. Overall results indicated increased nrf2, nqo1, ho1, mnsod expression at all time points and increased cyp1a expression after 60 days exposure. Emphasizing on the Nrf2-Keap1 pathway, this study exhibited additive or sometimes synergistic effects of As and Cr in zebrafish liver.

Miliary Tuberculosis as Postmortem Diagnosis in Solid Organ Transplant Recipient: Case Report and Review of the Literature

The diagnosis of tuberculosis (TB) in solid organ transplant (SOT) recipients presents challenges that may lead to treatment delay. These include atypical clinical presentations, increased likelihood of negative tuberculin skin test or/and interferon-gamma release assays, and negative sputum smear results despite active disease. The treatment poses challenges due to pharmacokinetic interactions, allograft-related toxicity, and inadequate immune response. We report the case of a 70-year-old man after kidney transplantation in 2012. The patient was transferred from the urology unit with deteriorating renal function and presumed urosepsis. His pulmonary chest X-ray showed hilar pulmonary infiltrates. Computed tomography of the chest/abdomen/pelvis revealed mediastinal lymphadenopathy, pulmonary infiltrates, pulmonary effusion, and splenomegaly. His blood results showed pancytopenia and high inflammatory and renal markers. He was treated with broad-spectrum antibiotics covering bacterial, fungal, and viral infections. Despite initial clinical improvement, his kidney function deteriorated, and he required hemodialysis. His temperature continued to spike. On physical examination, he was confused and lethargic. He was scheduled to have a mediastinoscopy with lymph node biopsy, but he died the day before. The postmortem examination revealed miliary tuberculosis with tuberculosis of many organs: kidney transplant, native kidney, bone marrow, mediastinal lymph nodes, lungs, and spleen. The diagnosis of active TB in transplant recipients requires a high index of suspicion and invasive procedures. The majority of all cases of active TB after SOT are disseminated or occur at extrapulmonary sites. Only a small minority of patients have classic cavitary changes on pulmonary imaging.

Implications of tolerance to iron toxicity on root system architecture changes in rice (Oryza sativa L.)

IntroductionToxicity due to excess soil iron (Fe) is a significant concern for rice cultivation in lowland areas with acidic soils. Toxic levels of Fe adversely affect plant growth by disrupting the absorption of essential macronutrients, and by causing cellular damage. To understand the responses to excess Fe, particularly on seedling root system, this study evaluated rice genotypes under varying Fe levels.MethodsSixteen diverse rice genotypes were hydroponically screened under induced Fe levels, ranging from normal to excess. Morphological and root system characteristics were observed. The onset of leaf bronzing was monitored to identify the toxic response to the excess Fe. Additionally, agronomic and root characteristics were measured to classify genotypes into tolerant and sensitive categories by computing a response stability index.ResultsOur results revealed that 460 ppm of Fe in the nutrient solution served as a critical threshold for screening genotypes during the seedling stage. Fe toxicity significantly affected root system traits, emphasizing the consequential impact on aerial biomass and nutrient deprivation. To classify genotypes into tolerant and sensitive categories, leaf bronzing score was used as a major indicator of Fe stress. However, the response stability index provided a robust basis for classification for the growth performance. Apart from the established tolerant varieties, we could identify a previously unrecognized tolerant variety, ILS 12–5 in this study. Some of the popular mega varieties, including BPT 5204 and Pusa 44, were found to be highly sensitive.DiscussionOur findings suggest that root system damage, particularly in root length, surface area, and root volume, is the key factor contributing to the sensitivity responses under Fe toxicity. Tolerant genotypes were found to retain more healthy roots than the sensitive ones. Fe exclusion, by reducing Fe2+ uptake, may be a major mechanism for tolerance among these genotypes. Further field evaluations are necessary to confirm the behavior of identified tolerant and sensitive lines under natural conditions. Insights from the study provide potential scope for enhancement of tolerance through breeding programs as well as throw light on the role root system in conferring tolerance.

Toxicological evaluation of a fish oil concentrate containing Very Long Chain Fatty Acids

Very long chain fatty acids (VLCFA) have a chain length ≥24 carbons. Fish contain low levels of these fatty acids. A commercial oil called EPAX® Evolve 05 with an up-concentration of VLCFAs of approximately 10 times, has been developed as a dietary supplement by Epax Norway AS. A series of toxicological studies were performed using mice and rats to determine the safety and toxicity of repeat dosing with a gavage administered VLCFA formulation. The results suggest transient lipid accumulation in kidneys and liver. Lipid accumulation was seen with the test item and with the soya control but was not dose related. Liver and kidney lipid accumulation, whilst present in 14- day repeat dose study, was absent in a 90-day rat study. No treatment-effect was seen in urine analysis in any of the studies. No treatment-related effects were seen with a functional observation battery, ophthalmological examination, haematology, urine analysis, oestrus cycle, thyroid hormones, organ weight, or histopathology. In the 90-day study the liver enzymes ALP, AST and ALT were statistically significantly increased with test item but within control values. There were no associated histological findings in the liver suggesting there was no toxic effect and the normalisation of values for all liver enzymes in the recovery groups suggests an adaptive response rather than a prevailing toxic response. The no-observed-adverse-effect level (NOAEL) was determined as 1200 mg VLCFA/kg b.w./day.

Threats of nano/microplastics to reproduction and offspring: Potential mechanisms and perspectives

Due to the ubiquitous occurrence in the aquatic environment and terrestrial ecosystem and underlying eco-environmental risks, nano/microplastics (NPs/MPs) have sparked great public concerns. The purpose of this work is aimed to summarize the harmful influence of NPs/MPs on reproduction and offspring health and further explore the potential mechanisms of action, thereby facilitating the more comprehensive understanding of NPs/MPs features. Literature search databases included EMBASE, Web of Science, and PubMed. The study selection and data extraction were implemented according to the inclusion criteria. NPs/MPs could accumulate and trigger reproductive toxic responses and thereafter generate deleterious effects on the offspring health. Accordingly, the reproductive toxicity of NPs/MPs was characterized as the sperm deformity, decline in sperm count and motility, follicular growth tardiness, ovarian fibrosis, granulosa cell death, disorder of reproductive hormone secretion, as well as the fetal growth restriction, glycolipid metabolism disorder, and inflammatory responses of the next generation. Additionally, mechanism research revealed that NPs/MPs exposure brought about inflammatory responses and oxidative stress and thereafter, destroyed the blood-testis barrier (BTB) integrity, motivated spermatogenic cell apoptosis by activating the JNK and p38/MAPK-Nrf2/NF-κB pathways, and induced ovarian granulosa cell pyroptosis and apoptosis and subsequent ovarian fibrosis via the Wnt/β-Catenin and NLRP3/Caspase-1 pathways. Nevertheless, this work also highlighted the imperative requirements for scientific and systematic risk assessments of NPs/MPs, so as to identify the feasible risk mitigation strategies.

CFTR is required for zinc-mediated antibacterial defense in human macrophages

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and E. coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E. coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.

Tau depletion in human neurons mitigates Aβ-driven toxicity

Alzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt−/− mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.

Oxidative stress and inflammatory markers in streptozotocin-induced acute and subacute toxicity response

Streptozotocin (STZ) is used as a diabetes-inducing agent in experimental animal studies. However, it is known that STZ-induced diabetic animals show significant increases in oxidative stress parameters and neurodegeneration besides their blood glucose level. In this study, the acute and subacute toxic effects of STZ on the liver, sciatic nerve, and brain tissues were investigated in vivo rat model. Sprague-Dawley rats were divided into two groups; while 50 mg/kg STZ was administered ip to the STZ group, only saline was administered to the control group. After STZ administration, three units (100 U/mL) of subcutaneous insulin glargine were applied daily to prevent the formation of diabetes. At 24 h, 1,2, and 4 weeks after applications, rats from each group were sacrificed and tissues were removed under anesthesia. At the end of the study, compared to the control, a significant decrease in SOD and GST activity and an increase in lipid peroxidation were detected in the liver and sciatic tissues of rats in the STZ-treated group in the first 24h. Considering the TUNEL, NFκB, and NOS2 expressions, it was noted that while the effects of STZ on the liver were observed in the acute stage (24h), it had subacute effects on the brain. When apoptosis-related gene expression (Bcl-2, Bax, CASP3, CASP8, CASP9, TNF-α) and immunohistochemistry were evaluated, the apoptotic effect of STZ was observed mostly in sciatic nerve tissues. Within the scope of the study, it was revealed that STZ did not only show selective toxicity to pancreatic β cells but also very toxic to other tissues and organs.

Heavy Metals Pollution and Other Physicochemical Parameters in the Crude Oil-Impacted Santa Barbara River and Environs, Bayelsa State, Nigeria

Higher levels of heavy metals in aquatic environments are most likely influenced by crude oil spills which may induce significant risk of heavy metal toxicity in aquatic species and humans. This research evaluated the levels of heavy metals and other physicochemical parameters in the crude oil-impacted Santa-Barbara River and environs of Bayelsa State, Nigeria. Heavy metals and other physicochemical parameters were examined using standard methods. Heavy metal pollution status was then deduced with standard pollution indicators. The water and fish samples collected from crude oil-impacted Santa Barbara River were heavily and moderately contaminated with iron, respectively (Igeo index = 4.29 and 2.87 for water and fish, respectively) and highly polluted with examined heavy metals (PLI = 4.29 and 1.13 for water and fish, respectively). The water samples from hand-dug wells were moderately contaminated with iron (Igeo index = 2.87) with overall low pollution by heavy metals (PLI = 0.46), while fish sold in neighboring communities was moderately contaminated with iron (Igeo index = 2.98) with overall moderate pollution by heavy metals (PLI = 0.86). However, potential ecological risks mediated by examining heavy metals in all water and fish samples were generally low (RI &lt; 40). The total dissolved solids, biochemical oxygen demand, nitrate and phosphate concentrations in all water samples were within permissible limits of WHO and FEPA. The ecological risks associated with water and fish from all sampling locations were deduced as low, mainly because iron was the most abundant heavy metal contaminant with no significant toxic response.

Toxic responses of metabolites produced by Ostreopsis cf. ovata on a panel of cell types

Blooms of the dinoflagellate Ostreopsis cf. ovata are regularly associated with human intoxications that are attributed to ovatoxins (OVTXs), the main toxic compounds produced by this organism and close analogs to palytoxin (PlTX). Unlike for PlTX, information on OVTXs'toxicity are scarce due to the absence of commercial standards. Extracts from two cultures of Mediterranean strains of O. cf. ovata (MCCV54 and MCCV55), two fractions containing or not OVTXs (prepared from the MCCV54 extract) and OVTX-a and -d (isolated from the MCCV55 extract) were generated. These chemical samples and PlTX were tested on a panel of cell types from several organs and tissues (skin, intestine, lung, liver and nervous system). The MCCV55 extract, containing a 2-fold higher amount of OVTXs than MCCV54 extract, was shown to be more cytotoxic on all the cell lines and more prone to increase interleukin-8 (IL-8) release in keratinocytes. The fraction containing OVTXs was also cytotoxic on the cell lines tested but induced IL-8 release only in liver cells. Unexpectedly, the cell lines tested showed the same sensitivity to the fraction that does not contain OVTXs. With this fraction, a pro-inflammatory effect was shown both in lung and liver cells. The level of cytotoxicity was similar for OVTX-a and –d, except on intestinal and skin cells where a weak difference of toxicity was observed. Among the 3 toxins, only PlTX induced a pro-inflammatory effect mostly on keratinocytes. These results suggest that the ubiquitous Na+/K+ ATPase target of PlTX is likely shared with OVTX-a and -d, although the differences in pro-inflammatory effect must be explained by other mechanisms.

Loco-regional radiotherapy in de novo metastatic nasopharyngeal carcinoma with chemotherapy and immunotherapy: A real-world retrospective study from two cancer centers.

Immunochemotherapy has become the first-line treatment for initial diagnosed metastatic nasopharyngeal carcinoma (mNPC). Loco-regional radiotherapy combined with systemic chemotherapy significantly improves the survival. However, the safety and efficacy of loco-regional radiotherapy combined with immunochemotherapy remained unknown. Patients with de novo mNPC who received immunochemotherapy followed by loco-regional radiotherapy were included from two cancer centers. Toxicity and treatment response were assessed using CTCAE 5.0 and RECIST 1.1, respectively. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. From 2019 to 2021, a total of 16 patients were retrospectively analyzed. The median follow-up was 28 months (range 14-47 months). No one died. One-year, 2-year, and 3-year PFS rate was 93.8%, 58.4% and 50.1%, respectively. Radiotherapy-related acute severe (grade 3 or higher) toxicity was dermatitis (1/16, 6.3%) and mucositis (2/16, 12.5%). Loco-regional radiotherapy provided a promising efficacy with modest toxicity for patients with mNPC who received immunochemotherapy.

A generalized Bayesian optimal interval design for dose optimization in immunotherapy.

For novel immuno-oncology therapies, the primary purpose of a dose-finding trial is to identify an optimal dose (OD), defined as the tolerable dose having adequate efficacy and immune response under the unpredictable dose-outcome (toxicity, efficacy, and immune response) relationships. In addition, the multiple low or moderate-grade toxicities rather than dose-limiting toxicities (DLTs) and multiple levels of efficacy should be evaluated differently in dose-finding to determine true OD for developing novel immuno-oncology therapies. We proposed a generalized Bayesian optimal interval design for immunotherapy, simultaneously considering efficacy and toxicity grades and immune response outcomes. The proposed design, named gBOIN-ETI design, is model-assisted and easy to implement to develop immunotherapy efficiently. The operating characteristics of the gBOIN-ETI are compared with other dose-finding trial designs in oncology by simulation across various realistic settings. Our simulations show that the gBOIN-ETI design could outperform the other available approaches in terms of both the percentage of correct OD selection and the average number of patients allocated to the OD across various realistic trial settings.

Molecular marker identification, antioxidant, antinociceptive, and anti-inflammatory responsiveness of malonic acid capped silver nanoparticle.

Nano-sized silver has drawn a great deal of attention in the field of health sciences owing to its remarkable therapeutic applications. Interestingly, the method applied to synthesize nanoparticles and the choice of reagents considerably influence their therapeutic potential and toxicities. Current research has explored the toxicity, anti-inflammatory, antinociceptive, and antioxidant responses of the malonic acid-capped silver nanoparticles (MA-AgNPs (C) by using sodium borohydride as a reducing agent at low temperatures by employing both in vitro and in vivo approaches. Furthermore, it has highlighted the synergistic effect of these novel compounds with conventional anti-inflammatory therapeutic agents. Acute and sub-acute toxicity analysis performed following OECD guidelines showed that the studied MA-AgNPs (C) are safer, and prominent toxic signs have not been detected at the highest studied dose of 2,000mg/kg. Cytotoxicity evaluation through brine shrimp lethality revealed 20% lethality at the highest concentration of 169.8μg/mL. Significantly, positive anti-inflammatory and analgesic responses alone as well as synergism with the standard were identified through in vitro as well as in vivo methods which were more potent at a lower dose (200mg/kg). Notably synergistic outcomes were more pronounced than individual ones, indicating their prominent effect as a feasible drug delivery system. IL-6 and TNF-α assessment in excised paw tissue through RTPCR technique further supported their anti-inflammatory potential. DPPH assay revealed eminent in vitro antioxidant activity which was further corroborated by in vivo antioxidant assessment through evaluation of SOD in excised paw tissue.

Modulating the immunosuppressive tumor microenvironment: Multi-synergistic cancer therapeutic approach with oncolytic viruses

Most patients with complex malignancies show a high level of toxicity and limited long-lasting responses to current conventional therapies. In contrast, the immune system has the intrinsic potential to distinguish between self and non-self (foreign or different) cells, including cancer cells, and successfully eliminate them. Even after T and NK cells successfully navigate sophisticated surveillance paths studded with diversion networks, processes, and impediments, they must overcome the impacts of a highly neutralizing and immune-suppressive destination known as the tumor microenvironment (TME). A comprehensive understanding of these TME events, immune system stimulative OVs functions, and synergistic possibilities with other immune activating strategies will provide insight and present a unique opportunity for improved therapeutic efficacy against cancer. The synergistic potential of combining oncolytic viruses with immune checkpoint inhibitors merits further exploration. In particular, focusing on the PD-1/PD-L1 (programmed cell death) axis may hold promise in amplifying antitumor immune responses and thereby bolstering therapeutic outcomes.