Toxic Effects Research Articles

The effect of smoking on amylase enzyme activity in saliva

Smoking has become a common habit in Indonesia. If done regularly, smoking is known to cause problems in the oral cavity. When smoking, cigarette smoke will enter the oral cavity and affect the activity of the salivary amylase enzyme. The journal search used in this review was conducted on several databases, such as PubMed, ScienceDirect, and Google with a range of years between 2013 and 2023. A total of 14 studies from various global populations were included in this review. Thirteen studies showed an association between smoking and alpha-amylase enzyme activity, while one study did not show an association between smoking and amylase enzyme. Of the 13 studies that showed an association, ten studies showed a negative association, while the remaining three studies showed a positive association. The effect of cigarettes on amylase activity in saliva may arise due to several factors, including the toxic effects of cigarettes on the salivary glands, mechanical and chemical stimulation of cigarettes on the mucosa, smoking period, oxidative stress index, and salivary pH.

Chronic toxicity and intergenerational effects of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) exposure alone and in combination with Zn2+ on Daphnia magna (Cladocera).

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and Zn2+, extensively used in the tire manufacturing process, are frequently detected in freshwater environments. However, the intergenerational effects of isolated 6PPD exposure and joint 6PPD and Zn2+ exposure at concentrations approximating environmental levels remain unknown. This study assessed the chronic toxicity and intergenerational effects of 6PPD (0.02-20 μg/L) and a mixture of 6PPD and Zn2+ (5 μg/L) over three generations in Daphnia magna bioassays. In the F0 generation, a dose-dependent decline in total offspring number was observed with 6PPD exposure alone, while co-exposure with Zn2+ exacerbated the reproductive toxicity of 6PPD. Across three generations, low-dose (0.02 µg/L) 6PPD alone and combined with Zn2+ induced a cumulative degenerative maternal effect. Conversely, high-dose (20 µg/L) 6PPD, both independently and in combination with Zn2+, exhibited an adaptive maternal effect. Notably, the grandmaternal effect emerged exclusively in the co-exposure group treated with 20 μg/L 6PPD and 5 μg/L Zn2+, with no such effect in the group exposed to 20 μg/L 6PPD alone, suggesting that Zn2+ may enhance the potential toxicity of 6PPD. Overall, this study provides novel insight into the intergenerational impacts of environmentally relevant levels of 6PPD alone and in combination with a heavy metal, elucidating the environmental risks posed by tire-derived chemicals through their synergistic effects on transgenerational toxicity.

Development of dihydropyrimidine based chemosensor for Hg2+ ions

The detection and monitoring of heavy metal ions in water media is critical due to their toxic effects on human health and the environment. In this study, we propose a green approach for synthesizing a dihydropyrimidine-based ligand by utilizing the concept of the Biginelli reaction and incorporating Ag nanoparticles as activators. This synthesized ligand demonstrates exceptional potential as a chemosensor for detecting poisonous Hg2+ ions using a simple spectrofluorometer tool. The ligand exhibits high selectivity and sensitivity towards Hg2+ over other transition metal ions in aqueous solution. This innovative method aligns with green chemistry principles, emphasizing the importance of using a straightforward and efficient sensing method of fluorescence. This is the first report where a dihydropyrimidine-based moiety detects toxic heavy metal ions, Hg+2(minimum detection level is 5X10−7 M).

Effects of atrazine, diuron and glyphosate mixtures on zebrafish embryos: acute toxicity and oxidative stress responses.

Synthetic pesticides are known for their toxic effects on non-target aquatic organisms. However, little is known about their effects when present in mixtures, which are closer to realistic exposure scenarios. Therefore, this study evaluates the toxicity of pesticides such as diuron, atrazine and glyphosate, individually and in combination, in zebrafish embryos, investigating their mechanisms of oxidative stress. The results revealed acute toxicity for diuron and atrazine, with LC50 values of 9.6 mg/L and 53.57 mg/L for 96-h-old zebrafish, respectively. On the other hand, no effect was observed for glyphosate alone at the maximum concentration tested (100 mg/L). The mixture of diuron and atrazine showed a synergistic effect, resulting in a decrease in the LC50 of each pesticide. Mixtures of diuron + glyphosate and atrazine + glyphosate were considered additive and antagonistic, respectively. All biomarkers analyzed (AChE, LDH, GST, CAT and GPx) showed significant changes. Furthermore, an increase in ROS production was observed in larvae exposed to individual and in the mixture composed of atrazine and diuron. These findings indicate that atrazine and diuron exhibit increased toxicity when combined, with their mechanisms of action-both in isolation and in mixtures-being at least partially linked to oxidative stress.

Bisphenol A and Its Emergent Substitutes: State of the Art of the Impact of These Plasticizers on Oxidative Stress and Its Role in Vascular Dysfunction

The “One Health approach” has evidenced the significant impact of xenobiotic exposure to health, and humans are a relevant target for their toxic effects. Bisphenol A (BPA) exerts a ubiquitous exposure source in all ecosystems. Given its endocrine-disrupting and harmful consequences on health, several countries have enforced new regulations to reduce exposure to BPA. Cardiovascular diseases (CVDs) are complex conditions that lead to higher mortality worldwide, where family history, lifestyle, and environmental factors, like BPA exposure, have a remarkable contribution. This chemical compound is the most widely used in plastic and epoxy resin manufacturing and has been associated with effects on human health. Therefore, new-generation bisphenols (NGBs) are replacing BPA use, arguing that they do not harm health. Nonetheless, the knowledge about whether NGBs are secure options is scanty. Although BPA’s effects on several organs and systems have been documented, the role of BPA and NGBs in CVDs has yet to be explored. This review’s goals are focused on the processes of endothelial activation (EA)–endothelial dysfunction (ED), a cornerstone of CVDs development, bisphenols’ (BPs) effects on these processes through oxidant and antioxidant system alteration. Despite the scarce evidence on pro-oxidant effects associated with NGBs, our review demonstrated a comparable harmful effect on BPA. The results from the present review suggest that the biological mechanisms to explain BPs cardiotoxic effects are the oxidant stress ↔ inflammatory response ↔ EA ↔ ED → atherosclerotic plate → coagulation promotion. Other effects contributing to CVD development include altered lipid metabolism, ionic channels, and the activation of different intracellular pathways, which contribute to ED perpetuation in a concerted manner.

Bisphenol A impairs oocyte maturation by dysfunction of cumulus cells

Bisphenol A (BPA) is a well-known environmental endocrine disruptor that has detrimental effects on reproduction. This study aimed to investigate whether BPA exposure could disrupt the function of cumulus cells and influence oocyte maturation and development. Porcine oocytes at the germinal vesicle stage were exposed to BPA for 44 h. The results revealed that BPA exposure led to dysfunction in cumulus cells by inhibiting meiotic division, inducing endoplasmic reticulum stress, and disrupting steroid synthesis. Furthermore, BPA exposure significantly increased reactive oxygen species and caused abnormal distribution of mitochondria in the oocytes. Notably, matured oocytes in the MII stage from the BPA-exposed groups showed significantly reduced development to the blastocyst stage, along with increased autophagy and apoptosis. These findings suggest that cumulus-oocyte complexes are sensitive to BPA exposure during the germinal vesicle stage, and the toxic effects of BPA on cumulus cells can severely inhibit oocyte and parthenogenetic embryos development.

Effects of binary polymer-humic soil amendments on soil carbon cycle and detoxication ability of heavy metal pollution

BackgroundSynthetic hydrophilic polyelectrolytes are considered as perspective tools to optimize soil properties and find increasing applications in agricultural technologies. One possible polyelectrolyte-based soil conditioner that has shown promise for improving soil hydrophysical properties is hydrolyzed polyacrylonitrile (HYPAN), linear polyanion. Combinations of HYPAN with humic substances in binary polymer-humic soil amendment presumably could provide a synergistic impact. In this study we investigated the effects of HYPAN, two different potassium humates (from lignite and lignosulfonate), and binary compositions of HYPAN with humates in the ratios of 1:1 and 1:2, on soil microbiological activity. We applied polymer solutions (0.9% on a dry matter basis) in a lab experiment and examined how they affected soil respiration, microbial biomass, metabolic quotient, and the decomposition rate constant in soil–polymer mixtures. A concurrent set of studies involved spiking soil–polymer mixes with heavy metals (copper, zinc, lead and cadmium).ResultsIn uncontaminated soil–polymer mixtures both humates stimulated the activity of soil microorganisms, expressed in increased basal respiration, microbial biomass, and mitigation of HM toxicity. The effects of binary polymer-humic formulations and HYPAN were comparable to and close in size to those of humates. On the 90th day, humates increased microbial respiration by 54–77% and HYPAN alone by 30%. Binary compositions were more efficient when combined with humate from lignosulphonate. The maximum increase in microbial biomass was obtained with the same humate both in composition and alone (65 and 91 µg C g−1). Under conditions of HM contamination at the end of the incubation, the levels of microbiological parameters in HM spiked soil–polymer mixtures did not statistically differ from the uncontaminated control. Every polymer formulation helped to partially restore microbial activity while reducing the toxic effects of HM. In these circumstances, humate from lignite both by itself and in combination with HYPAN performed better. The quality of organic matter in both humates and HYPAN was the primary determinant of the impact of the examined amendments.ConclusionsCombination of natural humate and synthetic HYPAN stimulated the activity of soil microorganisms, increased their biomass and mitigated the toxicity of heavy metals present in the soil. This allows the use of binary HYPAN-humate formulations to improve the chemical and biological properties of soil and increase its productivity.Graphical

Fluopyram SDHI pesticide alters fish physiology and behaviour despite low in vitro effects on mitochondria

Pollution from pesticides is an increasing concern for human health and biodiversity conservation. However, there is lack of knowledge about some emerging molecules such as SDHI fungicides (succinate dehydrogenase inhibitors) that are widely used but potentially highly toxic for vertebrates. Boscalid, fluopyram, and bixafen are 3 frequent SDHI molecules commonly detected in surface waters, which may pose risks to aquatic species. This study aimed to (1) test the in vitro effects of SDHI on mitochondrial activities (inhibition of succinate dehydrogenase SDH, also named respiratory chain complex II) and (2) assess the in vivo effects of sublethal SDHI concentrations on fish physiology and behaviour over 96 hours of exposure, using Carassius auratus fish as a model species. Results show that bixafen and boscalid inhibited complex II activities in vitro as expected (bixafen > boscalid), while fluopyram had no in vitro effects. In contrast, in vivo studies showed that fluopyram strongly altered fish behaviour (enhanced activity, social and feeding behaviours), likely explained by reduced AChE enzymatic activity. In addition, fluopyram increased muscle lipid content, suggesting metabolic disruption. These findings raise serious concern about the toxic effects of SDHI pesticides, especially fluopyram, although its underpinning molecular mechanisms remain to be explored. We thus encourage further research on the long-term impacts of SDHI pesticides to improve existing regulation and prevent adverse effects on wildlife.

Biosynthesis and Characterization of Silver Nanoparticles and Simvastatin Association in Titanium Biofilms

Introduction: Simvastatin is an antilipidemic drug that has already demonstrated antibacterial activities on oral and non-oral microorganisms. Silver nanoparticles also exhibit antimicrobial properties, particularly for coating implant surfaces. In this study, we evaluated the effects of combining simvastatin with silver nanoparticles on the formation and viability of biofilms consolidated on titanium discs. Methods: Silver nanoparticles were first biosynthesized using the fungus Fusarium oxysporum and then characterized using Dynamic Light Scattering, X-ray Diffraction, Transmission Electron Microscopy, and energy dispersive spectroscopy. Species of Streptococcus oralis, Streptococcus mutans, Porphyromonas gingivalis, Methicillin-sensitive Staphylococcus aureus, and Methicillin-resistant Staphylococcus aureus were used and tested using Minimum Inhibitory Concentration assays with concentrations of silver nanoparticles and simvastatin alone and in combination. Biofilm inhibition and viability tests were performed on titanium surfaces. Toxicity tests were also performed on Galleria mellonella moth larvae. Results: The silver nanoparticles had a spherical shape without the formation of aggregates as confirmed by Transmission Electron Microscopy. Dynamic Light Scattering revealed nanoparticles with an average diameter of 53.8 nm (±1.23 nm), a polydispersity index of 0.23 and a zeta potential of −25 mV (±2.19 mV). The silver nanoparticles inhibited the growth of the strains tested in the range of 0.001592 and 63.75, while simvastatin alone inhibited the growth of the same strains in the range of 3.125–62.5 µg/mL. The antibacterial activity test of the combination of the two substances showed a reduction in the Minimum Inhibitory Concentration of about two to eight times, showing synergistic effects on Staphylococcus aureus and additive effects on Streptococcus oralis and Porphyromonas gingivalis. As for biofilm, sub-inhibitory concentrations of the combination of substances showed better antibacterial activity in inhibiting the formation of Streptococcus oralis biofilm, and this combination also proved effective in eradicating already established biofilms compared to the substances alone. The combination of silver nanoparticles and simvastatin showed low toxicity to Galleria mellonella moth larvae. Conclusions: The results presented indicate that the combination of the two substances could be an alternative for the prevention and reduction of biofilms on implants. These findings open up new possibilities in the search for alternatives for the treatment of peri-implant infections, as well as the possibility of using lower doses compared to single drugs, achieving the same results and reducing potential toxic effects.

Enhanced reactive oxygen species and metabolism are involved in the reduction of tribenuron-methyl residues in Tartary buckwheat mutants

Tartary buckwheat, known for its rapid growth, short growth cycles, and adaptability, is cultivated worldwide, particularly in East Asia and Eastern Europe. However, weed infestations severely impact yield and quality, and the absence of effective herbicides poses a considerable challenge to Tartary buckwheat production. To address this, we used ethyl methane sulfonate (EMS) mutagenesis to create a mutant population of Tartary buckwheat seeds. We applied a targeted screening process using the herbicide tribenuron-methyl (TM) to select mutants with reduced sensitivity to the herbicide. Integrative analysis of transcriptomic and metabolomic data indicated that TM primarily inhibited photosynthesis and amino acid biosynthesis pathways in sensitive plants, leading to toxicity. Conversely, resistant plants could reduce the toxic effects of TM on Tartary buckwheat by increasing antioxidant enzyme activity and enhancing secondary metabolic pathways such as flavonoid biosynthesis. TM also upregulated the expression of a gene encoding uridine diphosphate glucuronic acid transferase-like (FtUGT79L). Overexpression of FtUGT79L in Arabidopsis substantially increased total flavonoid content and improved the resistance of Arabidopsis to TM at the seedling and adult stages. The study provides insights into innovative approaches for breeding herbicide-resistant Tartary buckwheat germplasm and serves as an important reference for the development of herbicide-resistant varieties of other crops.

Hydrogen peroxide priming triggers splicing memory in grape berries.

Plants are highly sensitive to environmental changes, and alternative splicing (AS) has been described in many studies due to its important control role in stress response. Recent studies indicated that plants exhibit splicing memory to stress to effectively activate transcriptional adaptation. Hydrogen peroxide (H2O2), as a reactive oxygen species (ROS), has toxic effects on plants. However, it also has a significant effect on promoting early maturity of 'Kyoho' grape at low concentrations. To explore the mechanism of priming treatment of H2O2 showing better promotion effect, the RNA-Seq data of H2O2-primied and no-primied fruits were analyzed. The genes with H2O2 stress splicing memory were identified, accompanied by changes in H3K4me3 modification levels, and their splicing memory patterns were verified by PCR and agarose gel electrophoresis. This finding establishes a link between alternative splicing memory and fruit ripening under H2O2 regulation and contribute to develop the application of H2O2 in fruit ripening.

N-3 polyunsaturated fatty acids enhanced efficacy of cytarabine in iron-overloaded NALM-6 cells via apoptotic and oxidative pathways

Despite progress in treating acute lymphoblastic leukemia (ALL), the adverse effects of chemotherapy toxicity and iron overload from transfusions continue to affect patients' quality of life. Polyunsaturated fatty acids (PUFAs) exhibit both antitumor and anti-inflammatory properties in leukemia. This study investigated the influence of n-3 PUFA on the efficacy of cytarabine in cells with iron overload. Iron overload was induced in NALM-6 cells using ferric ammonium citrate (FAC) and quantified through atomic absorption spectroscopy (AAS). The impact of n-3 PUFA on NALM-6 cells' response to cytarabine was evaluated using MTT, lactate dehydrogenase (LDH), apoptosis, and cell cycle assays. Additionally, gene expression analyses were performed on apoptotic, anti-apoptotic, and inflammatory genes, along with oxidative stress markers such as reactive oxygen species (ROS) and malondialdehyde (MDA) levels. The administration of n-3 PUFA significantly enhanced the effectiveness of cytarabine in iron-overloaded NALM-6 cells, leading to increased LDH secretion, elevated apoptosis rates, and G1 phase cell cycle arrest. These effects were associated with the upregulation of apoptotic genes such as P53 and caspase-8, the downregulation of the anti-apoptotic gene Bcl2, and a decrease in the inflammatory gene TNF-α. Furthermore, there was a notable increase in ROS and MDA levels. Overall, n-3 PUFA treatment improved cytarabine's efficacy in iron-overloaded NALM-6 cells by activating apoptotic processes and oxidative stress pathways.

Green-synthesized silver nanoparticles induced apoptotic cell death in CACO2 cancer cells by activating MLH1 gene expression

MLH1 (Mult homolog1) gene is the main element of Multlα heterodimer and plays a role in the repair of base-base mismatches and deletion and addition loops. When the MLH1 protein is not present, the number of errors that remain unrepaired increases, and this can lead to the formation of tumors in the body. Colorectal cancer is the third most common type of cancer in terms of incidence and the third type of cancer in terms of mortality worldwide. In this regard, the present study was conducted with the aim of investigating the effect of biological silver nanoparticles with anticancer properties and MLH1 gene expression on cancer cell samples of people with colorectal cancer. In this study, the green synthesis of silver nanoparticles was carried out by precipitation method with reduction of silver ions by leaf and flower extract of Moringa oleifera plant. Then, silver nanoparticles were confirmed using UV-visible spectroscopy, transmission and scanning electron microscopy. The cytotoxic effects of nanoparticles on cells were evaluated by MTT colorimetric method within 42 h. After RNA extraction of treated cells, cDNA synthesis and primers were designed by the Exon-Exon Junction method and the Real-time Polymerase test for MLH1 and Beta-actin genes was repeated three times. The final analysis of the results was done using Graphpad Prism and Rest 2009 software. The presence of a peak at the wavelength of 234 nm for the synthesized silver nanoparticles was confirmed by ultraviolet-visible spectroscopic analysis. The morphological study on the size and shape of the silver nanoparticles showed that the nanoparticles are spherical and have a size between 40 and 34 nanometers in diameter. The leaf extract typically produces smaller, more uniform particles than the flower extract. The Green-Synthesized Silver Nanoparticles of leaf extract were used to evaluation of induced Apoptotic Cell Death in CACO2 Cancer Cells by Activating MLH1 Gene Expression. MTT results showed that the anti-proliferative effect of nanoparticles depends on the concentration of synthesized silver nanoparticles. The treatment of MLH1 cancer cell line and normal with synthesized nanoparticles at a concentration of 0.44 micrograms per ml for 42 h showed the effects of cell toxicity. The percentage of cancer cell death under the influence of quercetin present in Moringa green bio-particles depends on the concentration and time, and this difference is statistically significant compared to the control group (P < 0.05). So that the lethal dose of the extract for 50% survival IC50 in a period of 48 h for intestinal cancer cells was equal to 21 μg/ml, and the expression ratio of the MLH1 gene in the tumor tissue to the adjacent healthy tissue has increased (P ≤ 0.05).

Exploring the potential of 7,4′-di(diethylamino)flavylium as a novel photosensitizer for topical photodynamic therapy of skin cancer

Photodynamic therapy (PDT) is a minimally invasive therapeutic approach that has shown promising results in recent years, particularly in the dermatological clinical treatment of several pathologies, including neoplastic skin diseases. In light of the recent discovery of the photosensitizing properties of a water-soluble group of amino-based flavylium dyes, research efforts have led to the development of a novel synthetic dye with two diethylamino moieties in its structure, 7,4’-di(diethylamino)flavylium (7,4′diN(Et)2). This dye was tested as a potential photosensitizer for PDT of skin cancer. A single light dose of 22.5 J/cm2 efficiently killed SCC-25 (squamous cell carcinoma) and A375 (melanoma) cells, reducing cellular viability by more than 80% in the presence of the flavylium at 0.75 µM. Meanwhile, the negligible cellular toxicity of the dye in the absence of light stimulus points out a wide and safe therapeutic window. Interestingly, significant light-induced toxicity effects were still observed after washing out the compound before cell irradiation. Moreover, out of the three prototype flavylium-loaded hydrogels, each one based on a different polymer (Carbomer, Caesalpinia Spinosa Gum and Hydroxypropyl methyl cellulose), carbomer-based formulation stood out for its substantial absorbance and fluorescence increment and enhanced1O2 photogeneration activity compared to the flavylium in aqueous solution. The findings of this study provide valuable insights concerning the potential of this flavylium dye as a candidate for photodynamic therapy of skin cancer and strongly support the need for further testing in more advanced biological settings to fully assess its efficacy and safety.

Neuropathy and the metabolic syndrome

Obesity and the metabolic syndrome (MetS) are major global health challenges that contribute significantly to the rising prevalence of type 2 diabetes (T2D) and neuropathy. Neuropathy, a common and disabling complication of T2D, is characterized by progressive distal-to-proximal axonal degeneration, driven in part by mitochondrial dysfunction in both neurons and axons. Recent evidence points to the toxic effects of saturated fatty acids on peripheral nerve health, with studies demonstrating that these fats impair mitochondrial function and bioenergetics, leading to distal axonal loss. Conversely, monounsaturated fatty acids are found to be neuroprotective, restoring mitochondrial function and preventing neuropathy. These findings suggest that dietary factors play a crucial role in the pathogenesis of neuropathy associated with metabolic dysregulation and emphasize the need for lifestyle interventions and therapies that target these newly identified mechanisms.

Multi-omics analysis of the toxic effects on gill tissues of crucian carp (Carassius auratus) from chronic exposure to environmentally relevant concentrations of Di(2-ethylhexyl) phthalate (DEHP)

The pervasive use of the plasticizer di(2-ethylhexyl) phthalate (DEHP) poses potential risks to global aquatic ecosystems. This study systematically evaluated the adverse effects of chronic exposure to environmentally relevant concentrations of DEHP on gill tissues of crucian carp, utilizing histological examination, metabolomic, and transcriptomic analysis. The results demonstrated that DEHP induced significant histopathological alterations in gill tissues, with significant enrichment observed in multiple pathways associated with amino acid, hormone, lipid, and xenobiotic metabolism. Metabonomics-transcriptomics analyses indicated that DEHP-induced significantly over-activation of cytochrome P450 1B1-like (p < 0.001) and cytochrome P450 3A30-like (p < 0.05) via the nuclear xenobiotic receptors pathway was a key factor contributing to the disruption of tryptophan metabolism and steroid hormone biosynthesis, as well as inducing circadian rhythm disruption. Moreover, circadian rhythm disruption further exacerbated the imbalance of cytochrome P450 (CYP450) enzyme system as well as linoleic acid, arachidonic acid, sphingolipid, and glycerophospholipid metabolism. Overall, the feedback regulation between the CYP450 enzyme system and circadian rhythms emerged as the primary mechanism underlying DEHP-induced metabolic and transcriptional disruptions, ultimately resulting in gill toxicity. This study not only enriched the toxic effects on aquatic organisms of chronic exposure to DEHP, but provided potential biomarkers for the environmental risk assessment of DEHP.

Patient, Caregiver, and Clinician Perspectives on the Time Burdens of Cancer Care

Cancer and its care impose significant time commitments on patients and care partners. The oncology community has only recently conceptualized these commitments and the associated burden as the "time toxicity" of cancer care. As the concept gains traction, there is a critical need to fundamentally understand the perspectives of multiple stakeholders on the time burdens of cancer care. To explore time-consuming aspects of cancer care that were perceived as burdensome, identify the individuals most affected by time burdens of cancer care, and evaluate the consequences of these time burdens. Participants in this qualitative analysis were recruited from a National Cancer Institute-designated cancer center in Minnesota, where semistructured qualitative interviews were conducted from February 1 to October 31, 2023. Purposive and criterion sampling methods were used to recruit patients (adults with advanced stage gastrointestinal cancer receiving systemic cancer-directed treatment), care partners (patient-identified informal [unpaid] partners), and clinicians (physicians, physician assistants, nurse practitioners, nurses, social workers, and schedulers). Data were analyzed from February 2023 to February 2024. Thematic analysis was conducted with a hybrid (inductive and deductive methods) approach. Themes, subthemes, and illustrative quotations are presented. Interviews included 47 participants (16 patients [8 aged ≤60 years; 12 women (75.0%)], 15 care partners [12 aged ≤60 years; 9 women (60.0%)], and 16 clinicians [11 women (68.7%)]). A total of 31 subthemes were identified that were grouped into 5 themes. Theme 1 captured time burdens due to health care outside the home (eg, travel, parking, and waiting time), while theme 2 identified the often invisible tasks performed at home (eg, handling insurance and medical bills, receiving formal home-based care). Theme 3 explored how care partners are affected alongside patients (eg, burdens extending to the wider network of family, friends, and community) and theme 4 represented the consequences of time burdens (eg, demoralization, seemingly short visits turned into all-day affairs). Finally, theme 5 referenced positive time spent in clinical interactions and hope for change (eg, patients value meaningful care, the "time toxicity" label is a spark for change). This qualitative analysis identifies key sources and effects of time toxicity, as well as the populations affected. The results of this study will guide the oncology community to map, measure, and address future time burdens.

The interaction of adenosine and dopamine in modulating the consequences of central nervous system oxygen toxicity.

Hyperbaric oxygen (HBO) refers to pure oxygen with a pressure greater than 1 atmospheres absolute (ATA), and when the pressure is too high, it can cause convulsive attacks. Adenosine and dopamine have been shown to be closely associated with HBO induced convulsion seizures, and their receptors exhibited a coexisting relationship of mutual antagonism on the membrane of nerve cells. We explored the influence of adenosine and dopamine interplay on the occurrence of oxygen convulsion. Rats were individually exposed to HBO of 6 ATA and treated with adenosine, dopamine, and their receptor modulators separately and jointly, with the latency of convulsion onset recorded. Additionally, after administering adenosine to rats and exposing them to HBO for 30 min, the content of dopamine and its metabolites, as well as the activity of enzymes related to their metabolism, were measured. The results revealed that dopamine was effective in resisting convulsion (> 60 min vs 32.53±5.31 min, P=0.000), and low-dose adenosine partially counteracted its effect (> 60 min vs 28.18±6.24 min, P=0.002). The combined use of adenosine A1 and dopamine D1 receptor modulators significantly impacted the incidence of convulsion. The activation or inhibition of A2A receptor had a particularly significant impact on convulsion, while modulating D2 receptor did not affect their effects. The combination of A1 agonist and D2 agonist was highly effective in resisting convulsion (> 60 min vs 32.53±5.31 min, P=0.000). Exposure to HBO accelerated the metabolism of dopamine to its end products, which may be related to the enhanced activity of monoamine oxidase (MAO). Adenosine can inhibit MAO activity (0.0766±0.0150 U/mg.prot vs 0.1055±0.0086 U/mg.prot, P=0.004), maintaining a higher level of dopamine (1.820±0.379 mg/g vs 0.602±0.087 mg/g, P=0.000). The study demonstrated that dopamine plays a significant role in oxygen convulsion, and adenosine can affect dopamine metabolism. The interaction between them can have a crucial impact on the occurrence of oxygen convulsion. The findings offer a novel perspective for further investigating the mechanism of oxygen convulsion and exploring effective preventive strategies.

Erianin inhibits the progression of DDP-resistant lung adenocarcinoma by regulating the Wnt/β-catenin pathway and activating the caspase-3 for apoptosis in vitro and in vivo

BackgroundPlatinum-based chemotherapy is one of the main treatments for lung adenocarcinoma (LUAD). However, the toxic side effects and drug resistance of chemotherapeutic drugs on normal cells are still a thorny problem in clinical treatment. Dendrobium is one of the three largest genera of Orchidaceous family, which has ornamental and medicinal value. Dendrobium is mainly distributed in the tropics and subtropics of South Asia, Oceania and other regions, with 1547 species of Dendrobium currently known. In China, “Shi hu” and “Tie pi shi hu” are well-known traditional medicines and have been included in the Chinese Pharmacopoeia (Editorial Board of Chinese Pharmacopoeia, 2020). Erianin is a natural product isolated from Dendrobium and is considered as a potential anticancer molecule due to its remarkable anti-tumor effects through various mechanisms, among which induced cancer cell apoptosis, inhibited invasion and migration. This study preliminarily explored the mechanism of Erianin inhibiting the progression of cisplatin (DDP) resistant LUAD in vivo and in vitro.MethodsThe effect of Erianin on the proliferation of DDP-resistant LUAD cells was detected by CCK-8 assay, wound healing assay and cloning assay. Transwell assay was used to evaluate the effect of Erianin on cell invasion and migration. The changes of cell cycle and apoptosis were detected by flow cytometry and TUNEL assay. Finally, the effects of Erianin on cell function and signaling pathway-related protein expression in vivo and in vitro were examined based on the enrichment analysis.ResultsErianin could inhibit the proliferation, invasion and migration, induce apoptosis, altered cell cycle of DDP-resistant LUAD cells, and reverse the resistance to DDP. Western blotting results showed that Erianin exerted its anti-tumor effects by regulating the Wnt/β-catenin cascade in DDP-resistant LUAD cells.ConclusionErianin may exerted its anti-tumor effect in DDP-resistant LUAD cells by regulating the Wnt3/β-Catenin/Survivin/Bcl-2/Caspase-3/Cyclin D1 axis.

Therapeutic potential of synthetic and natural iron chelators against ferroptosis.

Ferroptosis, a regulated form of cell death, is characterized by iron accumulation that results in the production of reactive oxygen species. This further causes lipid peroxidation and damage to the cellular components, eventually culminating into oxidative stress. Recent studies have highlighted the pivotal role of ferroptosis in the pathophysiological development and progression of various diseases such as β-thalassemia, hemochromatosis, and neurodegenerative disorders like AD and PD. Extensive efforts are in progress to understand the molecular mechanisms governing the role of ferroptosis in these conditions, and chelation therapy stands out as a potential approach to mitigate ferroptosis and its related implications in their development. There are currently both synthetic and natural iron chelators that are being researched for their potential as ferroptosis inhibitors. While synthetic chelators are relatively well-established and studied, their short plasma half-life and toxic side effects necessitate the exploration and identification of natural products that can act as efficient and safe iron chelators. In this review, we comprehensively discuss both synthetic and natural iron chelators as potential therapeutic strategies against ferroptosis-induced pathologies.