Search Results (497)

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

Background/Objectives: Cytarabine (Ara-C) remains central to acute myeloid leukemia therapy but is limited by unpredictable systemic toxicities. Preclinical studies have long documented multi-organ injury, yet findings remain fragmented. This systematic review synthesizes animal evidence to clarify the spectrum, dose–response patterns, and mechanisms of cytarabine-induced toxicity. Methods: Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251081384), a comprehensive search of PubMed, MEDLINE, Scopus, Cochrane Library and Embase identified eligible in vivo animal studies. Data extraction covered animal models, dosing regimens, routes of administration, histopathological and biochemical endpoints and mechanistic findings. Risk of bias and study quality were assessed using SYRCLE’s tool, CAMARADES checklist and an adapted Newcastle–Ottawa Scale, with reporting benchmarked against ARRIVE 2.0. Results: Eighty-one studies (1964–2024) were included. Cytarabine produced dose- and regimen-dependent toxicities across multiple organs. Neurotoxicity was most frequently reported, followed by intestinal mucositis, ocular injury, alopecia, hepatotoxicity, nephrotoxicity, and developmental anomalies. Mechanistic analyses consistently implicated oxidative stress, inflammatory cascades, apoptosis, and epigenetic dysregulation. Study quality was moderate, with frequent deficiencies in randomization, blinding, and sample-size justification, raising concerns about reproducibility. Cardiotoxicity, despite clinical relevance, was virtually absent from preclinical evaluation. Conclusions: Preclinical evidence suggests cytarabine’s systemic toxicity as a multifactorial process extending beyond rapidly proliferating tissues. While animal studies provide mechanistic insights, methodological weaknesses and translational gaps limit predictive value. Future research must adopt rigorous design, systematically assess underexplored toxicities, and integrate molecular profiling to identify biomarkers and protective strategies. Full article

Beans are widely consumed worldwide and are a good source of amino acids and micronutrients; however, they contain anti-nutrients, such as lectins, tannins, protein inhibitors, saponins, and phytic acid, among others, which can reduce the food’s quality and cause adverse health effects. In this study, we analyzed the genotoxic and cytotoxic effects of a protein extract from Phaseolus acutifolius (TBE) seeds. The extract contained some antinutritional compounds, with a higher lectin content and an activity of 2701.85 HU. The acute toxicity test in mice showed that the extract was not lethal at the concentrations tested, as it did not cause any mortality. The in vitro cytotoxicity study on small intestinal epithelial cells indicated that the lectin-rich extract was cytotoxic in both assays, with IC₅₀ values of 10.08 µg/mL and 108.91 µg/mL for the free cell and intestinal fragment assays, respectively. In the in vivo study, an erythropoiesis-stimulatory effect was observed, with significant genotoxic damage noted at 48 h, evidenced by 11 micronucleated erythrocytes at 1000 mg/kg TBE. However, no genotoxicity was detected with prolonged treatment times. These results indicate that TBE is cytotoxic within the tested concentration range, and genotoxic damage is influenced by both concentration and exposure time. Full article

Natural deep eutectic solvents (NADES) have been extensively used for the extraction of a wide spectrum of plant materials. However, limited data about the in vivo toxicity of NADES extracts restrict their future practical application. In this study, we are aiming to assess the safety of a Sorbitol–lactic acid (3:1 mol./mol.; 30% water) NADES extract of Glycyrrhiza roots (GR) in mice. LC-MS/MS analysis revealed the presence of 17 metabolites, including phenolic acids, flavonoids, their glycosides, chalcones, terpene saponins, and coumarins. Interestingly, most of the identified compounds were found in higher amounts in NADES extract compared to water and EtOH extracts. No skin edema, inflammation, or erythema was observed in mice after topical application of NADES extract of GR and NADES at the doses of 50, 100, and 150 µL/mice in comparison with the control group. The calculated primary irritation index was about 0.45 both for NADES and NADES extract of GR only in high doses and falls into mild irritant categories. The individual Draize scores indicate that erythema was evident in the first three days and that all signs had disappeared by day five. No acute toxic signs or mortality of animals was observed in mice following oral administration of single doses of 4, 6, and 20 g/kg of NADES or NADES extract of GR. The NADES and extract seem to be safe at doses of up to 20 g/kg, and the LD50 was considered to be >20 g/kg. Our results open prospects for the use of NADES extract of GR for the development of transdermal and peroral formulations in the cosmetic, food, and pharmaceutical industries. Full article

Turmeric (Curcuma longa L., Zingiberaceae) is a widely consumed spice and functional food valued for its bioactive constituents. Using an activity-guided strategy, this study identified the dichloromethane fraction as the most potent anti-inflammatory fraction, exhibiting markedly stronger inhibition of reactive oxygen species (ROS) production than ibuprofen (IC₅₀ $\le$ 0.4 vs. 11.2 μg/mL). Bioassay-guided purification yielded bisacurone (1), didemethoxycurcumin (2), and β-turmerone (3), with compounds 1 and 2 reported here for the first time in this fraction. Among them, β-turmerone displayed the strongest anti-inflammatory activity (IC₅₀ = 4.7 μg/mL), consistent with in silico docking and molecular dynamics analyses, revealing greater binding affinity and complex stability with myeloperoxidase (ΔG_bind = −20.90 vs. −18.89 kcal/mol for ibuprofen). Gas chromatography–mass spectrometry (GC-MS) profiling revealed a phytochemical profile dominated by turmerones and curlone, correlating with the observed bioactivity. None of the fractions exhibited acute toxicity in brine shrimp lethality assays, indicating a favorable preliminary safety profile. Our findings demonstrate the value of activity-guided isolation combined with computational validation for identifying turmeric-derived bioactives with promising nutraceutical potential, warranting further in vivo evaluation. Full article

Global kiwifruit production has been severely affected by Pseudomonas syringae pv. actinidiae (Psa), which causes kiwifruit bacterial canker. The main strategies for controlling this pathogen involve the use of copper-based compounds and antibiotics, which are insufficient and promote the development of bacterial resistance. Therefore, this study evaluates the efficacy of different botanical products obtained from wild-grown and in vitro-grown plants, with 25–75% hydroalcoholic extracts (ethanol–water; 0.7 L/ha) effectively reducing the symptoms of the disease in kiwifruit, both in vitro and in vivo during a growing season. Additionally, field trials confirmed that the formulations promote better fruit yield and quality, demonstrating through acute oral toxicity testing in rats that the botanical product administered has no toxicity, making these botanical products a promising and sustainable alternative strategy for combating plant pathogen-induced diseases in an environmentally friendly manner. Full article

Nitrated monoaromatic hydrocarbons (NMAHs) are emerging air pollutants commonly found in biomass burning (BB) and anthropogenic aerosols (AA). Despite their frequent deposition into aquatic systems, their ecotoxicity is still poorly understood. This study evaluates the toxicity of BB and AA aerosol extracts and their main NMAH constituents (nitrocatechols, nitrophenols, and nitrosalicylic acids) using in vitro (cellular uptake, cytotoxicity) and in vivo (algal growth inhibition, zebrafish embryo development) bioassays. Polar aerosol extracts showed higher toxicity than nonpolar ones, with stronger interaction via zebrafish organic anion Oatp1d1 than organic cation Oct1 transporter, indicating selective uptake. NMAHs and their relevant mixtures showed similar toxicity patterns as BB water extract, so NMAHs were identified as contributors to aerosol toxicity. Nitrocatechols stand out for their toxicity, showing the highest chronic toxicity in algae (IC₅₀: 0.6–1.1 mg/L) and acute cytotoxicity in fish cells (IC₅₀: 2.0–4.1 mg/L), possibly because they dominated the NMAHs composition of aerosols (BB: 80.6%; AA: 79.8%). Sublethal NMAH concentrations caused developmental disorders and altered lipid homeostasis in zebrafish embryos, indicating early physiological stress on higher organisms. These findings reveal NMAHs as significant ecotoxic components of BB and AA emissions which may pose an increasing threat to aquatic ecosystems following atmospheric deposition. Full article

The study focused on essential oils (EOs) of plant origin, which are of great interest to scientists in the context of medical applications due to their biological properties, such as antimicrobial, anti-inflammatory, antioxidant, and anticancer effects. The objective of the study was to determine chemical profiles and biological activities of the essential oils extracted from five mixtures (M1 [Thymus vulgaris, Ammi visnaga, Syzygium aromaticum, Citrus sinensis]; M2 [Thymus vulgaris, Ammi visnaga, Cinnamomum verum, Citrus sinensis]; M3 [Mentha pulegium, Lavandula angustifolia, Zingiber officinale, Citrus sinensis]; M4 [Mentha pulegium, Lavandula angustifolia, Cinnamomum verum, Citrus sinensis]; M5 [Ammi visnaga, Lavandula angustifolia, Zingiber officinale, Syzygium aromaticum]). Each mixture was derived from a blend of four selected plants used in traditional medicine in Mostaganem, Algeria. When selecting the best composition, the interactions between plant components were considered in terms of potential therapeutic benefits. The chemical compositions of the EO mixtures were analyzed using GC-MS. The acute toxicity of the EO mixtures was evaluated in vivo following oral administration. The sensitivity of the microorganisms to the EO mixtures was determined using the agar diffusion method. Virucidal testing was performed using the quantitative suspension method to determine virucidal activity, as described in the European standard for disinfectants used in the medical field. The antioxidant activity of the EO mixtures was evaluated using a model membrane system based on liposomes derived from soybean phosphatidylcholine. Chemopreventive activity was assessed in vitro using cell culture. The main compounds identified were carvacrol and thymol in M1; geranial, cinnamylaldehyde, and carvacrol in M2; pulegone and limonene in M3; geranial and cinnamylaldehyde and limonene in M4; and eugenol and caryophyllene in M5. The selection of the “best” blend depended on the biological activity deemed most critical for the specific application. Specifically, M3, M4, and M5 exhibited the strongest anti-HSV-1, anti-HAdV-5, and anticancer activity, respectively. In contrast, M1, a potent antioxidant, demonstrated the strongest antibacterial and anticancer activity. These results indicate that M1, M3, M4, and M5 EOs have promising applications in the pharmaceutical industry and medical research. Full article

Calotropis procera, known as “Silk cotton”, stands out for the presence of various classes of bioactive compounds responsible for its ethnopharmacological properties. The study aimed to conduct a phytochemical investigation, evaluating the in vitro and in vivo toxicity together with the antinociceptive potential of an n-butanolic fraction (FB) from the leaves. The crude ethanolic extract (CEE) was obtained by maceration in ethanol for 72 h. It was then partitioned using a gradual solvent sequence. The FB was analyzed by HPLC-ESI-MS/MS in negative mode and ¹H and ¹³C NMR. Toxicity was assessed by the erythrocyte hemolytic assay and acute oral toxicity test at a single dose of 300 mg·kg⁻¹. The antinociceptive effect was assessed by the acetic acid-induced abdominal writhing test and the formalin test in mice at doses of 3.75, 7.5 and 15 mg·kg⁻¹ per os. HPLC-ESI-MS/MS analysis identified flavonoids, phenolic acids, and the megastigmane roseoside, isolated for the first time in C. procera. The FB did not cause hemolytic effects or behavioral or physiological changes in mice. It showed an antinociceptive effect at all doses, reducing abdominal writhing by up to 91.46% and the licking time in phases 1 and 2 of the formalin test by up to 63.83% and 91.73%, respectively. In this study, it was possible to determine that an FB of a crude extract of C. procera leaves has antinociceptive activity, possibly associated with the phenolic compounds and roseoside found, with a lack of toxicity in vitro and in vivo, validating its ethnopharmacological use. Full article

The artificial breeding of fireflies is vital for supplementing natural populations. Unfortunately, mycosis is being observed with increasing frequency in the artificial breeding of fireflies, resulting in increased mortality. This study reports the identification of a microfungus that infects larval Pygoluciola sp., a species of semi-aquatic fireflies, during artificial breeding. Morphological and molecular analysis identified the fungi as Trichoderma koningiopsis (named as ZL01 strain). In addition, nystatin was selected out of five candidates as the optimal antifungal agent against T. koningiopsis ZL01, with a minimum inhibitory concentration of 25.00 μg/mL. Acute oral and contact in vivo toxicity tests on larval Pygoluciola sp. confirmed the safety of nystatin. Furthermore, compared to a Pygoluciola sp. larval population infected with T. koningiopsis ZL01, nystatin treatment increased the survival rate of larvae by twofold (spray administration) and threefold (drip administration) at the end of a nine-day artificial breeding experiment. These findings indicate that nystatin could be used as a potential antifungal agent to control mycosis in artificially bred fireflies. This study was the first to document the infection of semi-aquatic fireflies by pathogens and provide a corresponding treatment strategy. Full article

The production of β-lactamases is the main mechanism underlying carbapenem resistance. This study combined in silico and in vitro approaches to identify potential polyphenols as carbapenemase inhibitors. Molecular docking, molecular dynamics, and ADMET prediction were performed to assess the binding affinity, stability, and safety of quercetin, kaempferol, caffeic acid, and 3,4-dihydroxybenzoic acid against KPC-2, NDM-1, and OXA-48 carbapenemases. In vitro antibacterial assays and checkerboard analyses were conducted against Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa to assess antibacterial and synergistic effects. Then, the inhibition of the β-lactam hydrolytic activity was confirmed. In silico results showed that quercetin, kaempferol, and caffeic acid exhibited strong binding affinity and consistent stability towards the targets. Therefore, quercetin and kaempferol showed the strongest affinities (−8.0 kcal/mol) and stable interactions with key catalytic residues. ADMET profiles indicated good pharmacokinetic behavior and low acute toxicity. In vitro assays revealed that the polyphenols exhibited MIC values ranging from 12.5 to 25 mg/L and MBC values of 25–50 mg/L. Combined with cefotaxime, they enhanced bacterial susceptibility and inhibited β-lactam hydrolysis, with quercetin achieving complete inhibition at 200 mg/L. These findings highlight the potential of the four polyphenols as natural β-lactamase inhibitors. Further enzyme kinetics and in vivo studies are needed to confirm their therapeutic relevance. Full article

In China, bites caused by the Naja atra and Deinagkistrodona acutus are the most common types of snakebites. While the functional characteristics of the two venom components have been well documented, their in vivo metabolic pathways, target organ distribution patterns, and dynamic pharmacokinetic profiles remain less explored. This study established a murine envenoming model through CY7-SE labeling of Naja atra and Deinagkistrodon acutus venoms. The real-time in vivo absorption and biodistribution of venoms were dynamically monitored via fluorescence imaging, with subsequent proteomic profiling to characterize organ-specific toxin targeting patterns. Gel filtration chromatography and HPLC analyses validated labeling efficiency at ratios of 0.1 mg CY7-SE per 1 mg Naja atra venom and 0.075 mg CY7-SE per 1 mg Deinagkistrodon acutus venom, with electrophoretic confirmation of protein integrity and preserved 740 nm fluorescence excitation. Acute toxicity assays demonstrated no significant difference in LD₅₀ lethality between labeled and native venoms (p > 0.05). The intoxication models revealed species-specific pathophenotypes, i.e., CY7-Naja atra venom induced systemic weakness, tachypnea, and inflammatory necrosis in lung, myocardium, and liver, whereas CY7-Deinagkistrodon acutus venom provoked hemorrhagic diathesis. Both models exhibited marked leukocytosis, transaminitis, and elevated creatinine levels (p < 0.05). Fluorescence tracing uncovered distinct biodistribution kinetics: Deinagkistrodon acutus venom achieved peak organ accumulation at 3 h with rapid dissemination (24 h injection-site retention: 12.61%), contrasting with Naja atra venom’s delayed 6 h peak and prolonged renal sequestration (24 h injection-site retention: 60.9%). Target organ proteomic profiling identified Deinagkistrodon acutus-enriched thrombin-like enzymes and metalloproteinases in lung/liver/spleen, while Naja atra venom predominantly accumulated renal acidic phospholipase A₂ and weakly neurotoxic NNAM2. Full article

Momordica charantia L. (Cucurbitaceae) has been widely recognized for its pharmacological potential, although studies on its leaves remain scarce. In this study, the hydroethanolic leaf extract (MCHLE) was chemically characterized by LC–MS/MS, revealing the presence of octopamine, ferulate, vitexin-2-O-rhamnoside, and other bioactive phenolics. Toxicological evaluation in Wistar rats demonstrated that both acute (2000 mg/kg) and repeated oral administration (up to 400 mg/kg for 28 days) caused no clinical or behavioral signs of toxicity. Notably, treatment significantly reduced glucose and cholesterol levels, in addition to attenuating lipid peroxidation and enhancing antioxidant defenses. In vivo, MCHLE inhibited leukocyte and neutrophil infiltration in the LPS-induced peritonitis model, with efficacy comparable to dexamethasone. It also reduced TNF-α secretion and nitric oxide generation in peritoneal fluids. In vitro assays with LPS-stimulated RAW 264.7 macrophages confirmed these effects, showing dose-dependent inhibition of TNF-α, IL-1β, and NO production. Gene expression analysis further demonstrated downregulation of TNF-α and MAPK, with marked suppression of NF-κB transcripts. Collectively, these results suggest that MCHLE exerts anti-inflammatory activity by targeting both mediator release and upstream signaling pathways, while maintaining a favorable safety profile, supporting its potential for further investigation as a promising source of bioactive compounds. Full article

Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer’s disease. Flavonoids such as quercetin derivatives have emerged as promising neuroprotective agents. This study investigates the impact of 3-O-methylquercetin (3OMQ), a methylated quercetin metabolite, on Wnt/β-catenin signaling and its potential relevance in neurodegenerative disease models. Methods: The ability of 3OMQ to modulate Wnt/β-catenin activity was analyzed using a luciferase-based reporter assay in both neural and non-neural cell lines. Cell viability assays evaluated cytotoxicity at various concentrations. We mapped 3OMQ activity within the pathway using targeted cell signaling experiments. Docking and molecular dynamics simulations suggested glycogen synthase kinase 3β (GSK3β) as a putative target of 3OMQ. Finally, we employed a mouse model of acute amyloid-β oligomer (AβO) toxicity to assess the in vivo effects of 3OMQ on spatial memory and Wnt-related gene expression. Results: We compared the flavonoids quercitrin, quercetin, and 3-O-methylquercitrin (3OMQ) with pharmacologically active compounds in a gene reporter assay (TOPFLASH) using Wnt-sensitive RKO cells treated with Wnt3a-conditioned medium. XAV-939 and PNU-74654 showed inhibitory activity, while BIO, CHIR99021, quercitrin, and 3OMQ enhanced the Wnt/β-catenin pathway. Notably, 3OMQ potentiated this pathway at concentrations 5–10 times lower than quercitrin and outperformed 1 μM BIO at 10 μM without cytotoxicity, highlighting its remarkable potency. Mechanistically, 3OMQ acts downstream of initial membrane activation and upstream of the β-catenin destruction complex. Consistently, molecular docking indicates a strong interaction with GSK3, a central regulator of the pathway. In adult mice, 3OMQ administration prevented AβO-induced recognition memory deficits and favored normalization of Wnt-related gene expression. Conclusions: These findings identify 3OMQ as a potent positive modulator of the Wnt/β-catenin pathway, with both in vitro and in vivo neuroprotective effects. Targeting Wnt signaling with compounds such as 3OMQ holds promise for maintaining neuronal health and developing therapeutic strategies for neurodegenerative conditions. Full article

Background: Karwinskia humboldtiana (Kh) is a toxic plant that produces a fruit that, when ingested in large quantities, causes damage to the lungs, liver, kidneys, pancreas, and duodenum. Pancreatic damage was measured using a semiquantitative score, revealing that it is progressive and characterized by selective apoptosis and necrosis of the exocrine portion. However, renal injury has not been evaluated using injury scales and has only been reported descriptively. Pancreatic adenocarcinoma is one of the top five causes of cancer death in the United States, and options for its treatment are limited. One of the toxins extracted from the fruit (T-514) has been tested as a possible antineoplastic agent in various cancer cell lines. In order to preliminarily assess its possible usefulness against pancreatic cancer, we decided to re-evaluate kidney damage using a semi-quantitative scale, hoping to obtain a lesser injury intensity than that reported in the pancreas. Methods: We analyzed kidney samples from the same model of acute pancreatitis by Kh by semiquantitative scoring to compare the results with those previously reported in the pancreas, and performed a TUNEL assay to analyze cell death in the kidney. Results: The renal injury that occurs in this model of Kh poisoning consists mainly of hydropic degeneration and loss of microvilli in proximal tubules. According to the scale used in this work, the following percentages of kidney injury were obtained: 8.26 ± 0.93% for the control group, 9.65 ± 1.60%, 11.04 ± 1.36%, 12.78 ± 2.46%, 14.03 ± 1.83% and 15.76 ± 3.73% for the groups 24 h, 48 h, 72 h, 96 h and 120 h after Kh administration. In contrast, the following were reported for the pancreas: 0.28 ± 0.83% for the control group, 14.81 ± 7.64%, 35.63 ± 12.05%, 67.13 ± 5.27%, 85.28 ± 13.14% and 87.13 ± 11.17% for the groups 24 h, 48 h, 72 h, 96 h and 120 h after Kh administration. These results indicate that pancreatic injury is 71.37% more intense than renal injury at 120 h after Kh. No evidence of nuclear chromatin fragmentation was found in the kidney. Conclusions: The renal damage in this model of acute pancreatitis is of lower intensity than the pancreatic damage, suggesting that Kh and its toxins may be useful in the treatment of pancreatic cancer and their study in an in vitro or in vivo cancer model is justified. Full article