Search Results (1,110)

Dioryctria abietella (Lepidoptera: Pyralidae) is a destructive forest pest for coniferous trees. Bacillus thuringiensis has been widely applied in forestry as a biological control agent to control it. However, the mechanisms of Bt-induced mortality in D. abietella, particularly its effects on gene expression and enzyme activities, remain unclear. Here, bioassay, enzyme assay, transcriptome sequencing, and gene expression profiling were employed to explore the relationship between the toxin-receptor, defense, and lethal mechanisms of D. abietella after Bt exposure. In a toxicity bioassay, Bacillus thuringiensis galleriae 05041 strain (Bt05041) was the most toxic insecticide to the larvae of D. abietella, with LC₅₀ values of 3.15 × 10⁸ Colony-Forming Units (CFUs) mL⁻¹ at 72 h after treatment. Transcriptome analysis revealed that the gene expression patterns of D. abietella after 8 h of Bt05041 exposure (Bt8) varied considerably from the Bt05041-treated for 2 h group (Bt2). In the Bt2 group, differentially expressed genes were significantly enriched in cellular and bioenergy pathways of lysosome, insulin signaling, cGMP-PKG signaling, etc. Immune-related pathways were activated, namely cAMP, AMPK, MAPK, Rap1, IMD, and Toll pathways. Meanwhile, Bt8 treatment caused metabolic changes in basic substances such as amino acids, glucose, nucleic acids, and fatty acids. Bt05041 exposure activated the activities of defense enzymes and induced gene expression changes in D. abietella larvae. Among them, most Bt-receptor genes had higher expression levels than defense enzyme genes. Overall, these findings reveal a possible mechanism underlying Bt-mediated death in D. abietella larvae. This work provides valuable information in terms of biological control strategies. Full article

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Schistosomiasis, a neglected tropical disease affecting over 250 million people worldwide, relies on praziquantel (PZQ) as its sole treatment. However, PZQ has significant limitations, including inactivity against juvenile worms, inability to prevent reinfection, and emerging drug resistance. In this review, we outline the development of CIDD-0150303, a novel oxamniquine (OXA) derivative with pan-species and pan-stage activity against Schistosoma mansoni, PZQ-resistant S. mansoni, and S. haematobium. Using a structure-guided design approach, over 350 OXA analogs were synthesized and screened to identify leading drug candidate CIDD-0150303. CIDD-0150303 demonstrates 100% lethality in vitro and up to 80% reduction in worm burden in vivo. CIDD-0150303 is effective against both juvenile and adult parasites as well as PZQ-resistant S. mansoni. This compound represents a promising advance in schistosomiasis treatment to address urgent gaps in control/elimination strategies and PZQ resistance. However, dedicated safety and toxicity studies are still ongoing, and additional in vivo validation is required. Full article

This study compared the yield, percentage solids, electrophoretic profile, gelatinolytic activity, and brine shrimp lethality of Bitis arietans venom prepared using freeze-drying and desiccator drying. Bitis arietans venom was collected from snakes at Bioken snake farm, Kenya, whereafter it was pooled and divided into two parts. Part 1 was desiccator dried venom (DDV) while part 2 was freeze-dried venom (FDV). The yield and percentage solids in DDV and FDV were compared using Welch’s Student’s t-test and the dried venoms were subsequently subjected to sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), 2D electrophoresis, gelatin in-gel zymography, and brine shrimp lethality assays. Mean venom yield and percentage solids did not differ between DDV and FDV (p = 0.5647 and p = 0.4676, respectively). SDS-PAGE and two-dimensional (2D) electrophoresis revealed similar protein profiles for DDV and FDV, showing bands and spot clusters within molecular weight ranges of ~16 kDa to >150 kDa and pH ranging from 3.5 to 9.5. Enzyme zymography revealed comparable gelatinolytic activity between DDV and FDV. However, the brine shrimp lethality assay indicated significantly higher toxicity in DDV (LC₅₀: 86.57 μg/mL) compared to FDV (LC₅₀: 460.37 μg/mL). DDV also showed greater lethality than FDV at 100 μg/mL (p = 0.0416) and 1000 μg/mL (p = 0.0008) but not at 10 μg/mL (p = 0.2465). These findings suggest that DDV exhibits higher toxicity in brine shrimp larvae than FDV, although both drying methods result in similar yields, percentage solids, venom profile, and gelatinolytic activity. Further research is necessary to investigate the mechanism behind this difference and its implications for antivenom production and long-term stability of venom. Full article

Pancreatic, liver, gastric, colorectal, and rectal cancers (PC, LC, GC, CRC, and RC) are highly lethal tumours, with a 5-year survival rate of 10.5% (PC) and <20% (LC), and of 5%, 12%, and 13% for IV-stage GC, CRC, and RC, respectively. Currently, PC and LC represent the third leading cause of cancer-related death, while GCs and CRCs account for 4.8 million cancer cases and 4.4 million cancer deaths worldwide. Poor prognoses are mainly due to late diagnosis, limited efficacy of available treatments, tumour recurrence, as well as therapy-induced secondary tumorigenesis and drug resistance. In recent decades, these issues have been afforded using nanomaterials (NMs), with promising results. Carbon nanotubes (CNTs) are nonpareil nano systems, which have demonstrated high potential in both cancer diagnosis and treatment, showing to be excellent vehicles for drugs, antibodies, genes, etc. Used alone or in combination with available therapeutic strategies, such as photothermal, photodynamic, drug targeting, gene, immune, and chemotherapies, CNTs have shown notable results in laboratory settings, enhancing the anticancer effects and reducing toxic outcomes of traditional treatments. Anyway, despite PC, LC, and CRC being three of the five tumours (60%) considered the most perfidious and lethal cancers, studies on the use of these innovative NMs to cure them represent only 37% of those regarding the treatment of the most known tumours. Regarding this scenario of a worrying lack of efficient treatments for highly lethal PC, LC, GC, CRC, and RC, this umbrella review was drawn up to promote filling this gap in studies by reporting the still too limited and often obsolete experimentation on the possible use of CNTs for their diagnosis and therapy. To this end, such case studies have been collected in several informative Tables which are functional for readers, and the studies have been discussed. This study wants to sensitize scientists towards more extensive research to find novel safer applications of CNTs against PC, LC, GC, CRC, and RC, both in terms of early diagnoses and efficient treatments. Such efforts should also focus on clarifying the not yet fully unveiled toxicological aspects and regulatory hurdles, both of which persist around CNTs. Research should also be finalized to produce patents rather than journal articles, thus accelerating the translation of CNTs to clinical practice. Full article

Dithiocarbamate fungicides, including benomyl (methyl 1-butylcarbamoyl-2-benzimidazolecarbamate), share a common mechanism of toxicity by inhibiting aldehyde dehydrogenases (ALDHs), enzymes essential for detoxifying reactive aldehydes. One such aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), a dopamine metabolite, is implicated in the catecholaldehyde hypothesis of Parkinson’s disease. This study examines ALDH inhibition as the molecular initiating event (MIE) within an adverse outcome pathway (AOP) leading to neurotoxicity. Caenorhabditis elegans at the L4 stage were exposed for 24 h to 10 or 100 μM benomyl. While 10 μM had no significant effect on lethality, growth, or reproduction, 100 μM induced adverse effects, albeit with low lethality. Both doses inhibited ALH activity, an effect mitigated by Alda-1, a selective ALDH activator. Alda-1 alone increased ALH-1 protein levels but did not alter benomyl-induced protein localization and relative abundance. Benomyl exposure also elevated oxidative stress markers—superoxide dismutase, catalase, and lipid peroxidation—which Alda-1 reduced. Neurotoxicity was evidenced by dopaminergic dysfunction, including impaired basal slowing response, neuronal morphological abnormalities, and reduced locomotion upon optogenetic activation. Fluorescent reporter assays confirmed ALH-1 presence in dopaminergic neurons. These results identify ALH inhibition as the MIE in benomyl-induced neurotoxicity, linking dopaminergic degeneration and redox imbalance to the catecholaldehyde hypothesis, and providing mechanistic insights into an AOP relevant to neurodegenerative disorders. Full article

Pine wilt disease, which is induced by pine wood nematode (PWN, Bursaphelenchus xylophilus), has caused huge economic and ecological losses. To overcome the drawbacks of chemical control against PWN, twenty compounds were screened, and a synergistic botanical–chemical combination was identified. A proportion of abamectin to rotenone of 7:3 (5.73 and 1.78 mg/L, respectively) achieved the highest co-toxicity coefficient of 231.09 with a median lethal concentration of 3.18 mg/L. It revealed 0% mortality in Pinus massoniana seedlings at 60 days post-treatment when applied at 400 times the synergistic concentration (2.29 g/L abamectin + 0.71 g/L rotenone) at 7 days after PWN inoculation. Furthermore, the synergistic combination significantly affected the physiological activity and population dynamics of PWN. Female oviposition was reduced by 71.92%, the egg hatching rates declined to 13.09 ± 0.02%, and head thrashing frequency was inhibited by 99.23 ± 0.01%. The enzymatic activities of peroxidase, acetylcholinesterase, succinate dehydrogenase, and glutathione S-transferase were significantly increased, while the population size declined by 96.17%. Transcriptomic and gene expression analyses suggested a potential “Na⁺/Ca²⁺/Cl⁻ ionic storm,” since the synergistic combination significantly activated genes associated with voltage-gated calcium channels, glutamate-gated chloride channels, and amiloride-sensitive sodium channels. These findings provide an eco-friendly strategy for PWN management via chemical control. Full article

Compound T1089—a novel nitrogen mustard based on an indole-3-carboxylic acid derivative (ICAD)—has been synthesized. The ICAD used as the basis for T1089 is a TLR agonist capable of activating an antitumor immune response. This study describes the synthesis method and presents the results of preliminary investigations of this compound. This research included an assessment of acute toxicity in mice, in vivo clastogenic activity evaluated via the bone marrow chromosome aberration (BMCA) test in mice, in vitro cytotoxicity determined by the MTT assay against human lung carcinoma A549 cells, and in vivo antitumor effects (ATEs) in models of conventional chemotherapy (CCT) of solid tumors in mice. The bifunctional alkylating agent cyclophosphamide (CPA) was used as a reference drug. Toxicological studies revealed that T1089 belongs to toxicity class III (moderately toxic), with acute toxicity values (LD₁₆ and LD₅₀) in mice following intraperitoneal (i.p.) administration being 191 and 202 mg/kg, respectively. The alkylating activity and clastogenic potential of T1089 were demonstrated by its effects in the BMCA test, which were comparable to those of CPA. A single i.p. administration of CPA and T1089 at a dose of 0.064 mmol/kg induced similar stimulation of structural mutagenesis associated with DNA strand breaks. The frequency of karyocytes with aberrations increased 20-fold compared to the control, primarily due to a rise in chromatid breaks and fragments, and to a lesser extent, due to an increase in exchange-type aberrations. In vitro cytotoxicity studies indicated differences in the mechanisms of alkylating activity between CPA and T1089. According to the MTT assay, the cytotoxic effects of CPA were observed only at concentrations exceeding 2 mM (IC₅₀ = 4.2 ± 0.3 mM), corresponding to lethal in vivo doses, which is expected since the formation of CPA’s alkylating metabolite requires hepatic microsomal enzymes. In contrast, significant cytotoxic effects of T1089 were observed at much lower concentrations (15–50 μM, IC₅₀ = 33.4 ± 1.3 μM), corresponding to safe in vivo doses. Differences were also observed in the in vivo ATEs of CPA and T1089 in the Ehrlich solid carcinoma (ESC) CCT model. Following seven i.p. administrations at 48 h intervals (33 mg/kg), both compounds exhibited increasing toxicity, manifested as cumulative body weight loss in treated mice. However, despite the aggressive CCT regimen, ESC showed low sensitivity to CPA. The ATE of CPA developed slowly, reaching a significant level only after four injections, and even after seven administrations, tumor inhibition (TI) did not exceed 30%. In contrast, ESC was significantly more sensitive to T1089 under the same CCT conditions. The ATE of T1089 exhibited a cumulative pattern but developed more rapidly and to a greater extent. A significant antitumor effect was observed after just two injections, with maximal efficacy (TI = 53%) achieved after four injections and sustained until the end of the observation period. A high ATE of T1089 was also observed in the B-16 melanoma CCT model. Following six i.p. administrations at 48 h intervals (28 mg/kg), T1089 treatment was associated with minimal toxicity. Despite this mild CCT regimen, melanoma exhibited high sensitivity to T1089. Maximal ATE (TI = 56%) was achieved after two injections, and subsequent administrations maintained a consistently high efficacy (TI = 52–55%) until the end of the study. In summary, preliminary findings demonstrate that T1089 possesses alkylating activity characteristic of bifunctional agents, accompanied by high in vitro cytotoxicity and in vivo ATEs in CCT models (at high doses). Given that the ICAD used as the basis for T1089 is a TLR agonist capable of stimulating antitumor immunity, T1089 can be considered a dual-action alkylating agent with combined antitumor effects. These results justify further investigation of T1089 in conventional and metronomic chemotherapy regimens, particularly in combination with immune checkpoint inhibitors and antitumor vaccines. Full article

The spotted lanternfly (SLF), Lycorma delicatula (Hemiptera: Fulgoridae), has invaded several countries and caused significant losses to agricultural economy, especially in grapes, apples and kiwifruit production. Currently, chemical control is the primary method for managing this pest. In this study, we tested the contact toxicity of bifenthrin and lime sulphur on SLF eggs, as well as the residual toxicity of natural pyrethrins, bifenthrin, and thiacloprid on SLF nymphs. The results showed that bifenthrin, applied at 100 times the label rate, had the highest lethal effect on SLF eggs, with an adjusted mortality rate of 71.8 ± 8.5%. The addition of a penetrant, Engulf, did not further enhance ovicidal efficacy. For nymphs, the residual effect of thiacloprid and bifenthrin at label rates demonstrated 100% mortality within 48 h in laboratory bioassays. Similar efficacies were observed in short-term field experiments. However, the efficacy of bifenthrin declined significantly over time, while thiacloprid provided a long-lasting control, with mortality rates of 72.8 ± 5.9% and 46.7 ± 7.2% at 7 and 14 days, respectively. Although the combination of pyrethrins and mineral oil exhibited limited efficacy, with a 0-day (test immediately after the sprayed branches have dried) mortality rate of 41.5 ± 12.5%, its favourable environmental safety profile makes it a viable option for organic control strategies. In conclusion, bifenthrin at 100 times the label rate was the most effective against SLF eggs, while thiacloprid at label rates provided the longest-lasting control against SLF nymphs. Full article

Salinity, a critical environmental factor for fish survival, remains poorly understood in terms of how Triplophysa strauchii, a characteristic fish in Northwest China, physiologically responds to salinity stress. This study aimed to determine its salinity tolerance threshold and explore the associated physiological damage mechanisms. Six salinity gradients (11, 11.7, 12.5, 13.3, 14.3, 15.1 ppt) and a freshwater control group were established. Acute toxicity tests recorded mortality and behavior, while physiological–biochemical assays measured ion concentrations and enzyme activities in gills, kidneys, liver, intestines, and plasma over 96 h. The results showed a 96-hour median lethal concentration of 13.31 ppt and a safe concentration of 4.05 ppt. Gills and kidneys, as primary osmoregulatory organs, responded rapidly, whereas the liver and intestine lagged. Salinity ≤ 13.3 ppt allowed the fish to maintain homeostasis via physiological adjustments, but ≥14.3 ppt caused ion imbalance, immune function was significantly suppressed, and irreversible damage. These findings clarify the species’ salinity adaptation strategies, providing a basis for further research on chronic salinity stress. Full article

Although cannabinoids have proven therapeutic benefits, they are increasingly known for their capacity to disturb cardiac electrophysiology, particularly in individuals with hidden genetic issues such as channelopathies. This review consolidates molecular, clinical, epidemiological, and forensic findings linking cannabinoid exposure to arrhythmias and sudden cardiac death. It examines how phytocannabinoids, synthetic analogs, and endocannabinoids influence calcium and potassium currents through cannabinoid receptor-dependent and -independent pathways, affect autonomic regulation, and contribute to adverse conditions such as oxidative stress and inflammation in heart tissue. Genetic variants in key genes linked to SCD (SCN5A, KCNH2, KCNQ1, RYR2, and NOS1AP) can reduce repolarization reserve, transforming otherwise subclinical mutations into lethal substrates when combined with cannabinoid-induced electrical disruptions. Forensic research highlights the importance of comprehensive toxicological testing and postmortem genetic analysis in distinguishing between actual causes and incidental findings. There is an urgent need to re-evaluate the cardiovascular safety of cannabinoids, and this is underscored by the findings presented. The merging of molecular, clinical, and forensic evidence reveals that cannabinoid exposure—especially from high-potency synthetic analogs—can reveal latent channelopathies and precipitate fatal arrhythmias. Accordingly, this review advocates for a paradigm shift toward personalized risk stratification. If genetic screening is integrated with ECG surveillance and controlled cannabinoid dosing, risk assessment can be personalized. Ultimately, forensic and epidemiological data highlight the heart’s vulnerability, emphasizing its role as a target of cannabinoid toxicity and as a crucial aspect of public health monitoring. Full article

Nitrite is a common environmental pollutant in aquaculture systems, where high levels can severely impair fish physiology and survival. This study aimed to evaluate the acute toxicity of waterborne nitrite in starry flounder (Platichthys stellatus). Fish (mean weight 145.69 ± 16.06 g, mean total length 22.78 ± 0.70 cm) were exposed to nitrite concentrations of 0, 25, 50, 100, 200, 400, and 800 mg NO₂⁻/L for 96 h. The lethal concentration 50 (LC₅₀) of nitrite for P. stellatus was determined to be 574.47 mg NO₂⁻/L. Hematological parameters such as red blood cell counts (RBCs), hemoglobin (Hb), and hematocrit (Hct) were significantly decreased by nitrite exposure. Plasma components including calcium (Ca²⁺), glucose, cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly changed by nitrite exposure. The results of this study suggest that acute exposure to waterborne nitrite (>200 mg NO₂⁻/L) adversely affects survival rates, hematological parameters, and plasma components in P. stellatus. These findings provide important baseline data for nitrite toxicity assessment in P. stellatus. Full article

The fall armyworm, Spodoptera frugiperda, is a long-distance migratory pest, which invaded the African continent in 2016, causing enormous losses to agricultural crops, especially maize. Synthetic insecticides are primarily used for managing S. frugiperda, but they leave residues on human food and animal feed and also cause environmental hazards. We evaluated the crude ethanolic extract of Piper guineense fruits for contact toxicity on S. frugiperda larvae and determined the lethal concentration (LC₅₀) of the extract. Additionally, we conducted an electrophysiological (EAG) experiment to determine the responses of adult S. frugiperda males and females to P. guineense and determined whether the extract influenced mating, oviposition, and repellence to the adult female. We found that P. guineense extract caused significantly higher mortality to S. frugiperda larvae than an ethanol control. Electrophysiologically, we observed significantly higher responses to the extract than the control, with some variations in response between the sexes. A wind tunnel experiment revealed that females moved more towards the control than towards the extract. Taken together, our results confirm that P. guineense extract is effective against S. frugiperda larvae and adults. Future research should explore the responses of S. frugiperda to P. guineense extract on a field scale. Full article

Individuals with severe mental illness face a substantially higher risk of suicide compared with the general population, with drug overdose representing one of the most common and potentially lethal methods. This narrative review explores toxidromes frequently encountered in psychiatric populations, such as opioid, anticholinergic, and serotonergic toxicity, highlighting the clinical presentation in intentional overdose. Emphasis is placed on clinical recognition, antidote-based treatment, and systems-level strategies for the prevention of lethal overdose. We conducted a comprehensive literature search of PubMed, Google Scholar, and Web of Science for English-language articles using combinations of the following keywords: mental disorders; persons with psychiatric disorders; drug overdose; poisoning; serotonin syndrome; neuroleptic malignant syndrome; anticholinergic agents/poisoning; cholinergic antagonists/poisoning; psychotropic drugs/adverse effects; substance-related disorders; drug-related side effects and adverse reactions; polypharmacy; suicide, attempted; emergency service, hospital. By embedding toxidrome awareness into routine emergency and psychiatric practice, we aim to expedite treatment and improve patient outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due to late diagnosis, poor drug penetration, and intrinsic chemoresistance. Targeted delivery strategies are urgently needed to enhance therapeutic precision while minimizing systemic toxicity. Here, we developed an AS1411 aptamer-functionalized liposomal platform encapsulating siRNA against metastasis-associated protein 2 (MTA2), a chromatin remodeling factor that suppresses the tumor suppressor PTEN and activates PI3K/AKT signaling. The AS1411 aptamer, which binds nucleolin overexpressed on PDAC cells, was conjugated to cationic liposomes via copper-free click chemistry. The resulting AS1411-Lipm[siRNA] exhibited high siRNA encapsulation efficiency, selective uptake by nucleolin-positive PDAC cells, and enhanced endosomal escape. Treatment of MIA PaCa-2 cells with AS1411-Lipm[siRNA] significantly reduced MTA2 expression by ~60%, substantially restored PTEN, and inhibited AKT phosphorylation by ~50%, leading to decreased cell viability, impaired migration by ~75%, and increased apoptosis by ~35%, while sparing nucleolin-negative cells. These findings highlight AS1411-Lipm[siRNA] as a promising platform for selective siRNA delivery and potent molecular inhibition in PDAC therapy. Full article