Search Results (201)

The growing global protein demand and environmental concerns from conventional animal agriculture have driven the exploration of sustainable alternative protein sources. Single-cell proteins (SCPs) from microbial fermentation offer a promising solution. This study comprehensively evaluated the nutritional value and safety profile of SCP produced from Ralstonia eutropha H16 through integrated in vitro and in vivo assessments. Nutritional analyses revealed a high crude protein content of 71.87 ± 5.05 g/100 g dry weight, with total amino acids of 53.67 ± 1.05 g/100 g. The essential amino acid content was 24.38 ± 0.51 g/100 g, accounting for 45% of the total amino acids. An essential amino acid index (EAAI) of 1.46 ± 0.04 and an amino acid score (AAS) of 0.83 ± 0.06 confirmed its classification as a high-quality protein source according to FAO/WHO standards. In vivo rat feeding trials demonstrated an adjusted protein efficiency ratio (PER) of 1.81, exceeding common plant proteins such as wheat (0.8–1.1). True digestibility (TD) reached 85.73%, with a biological value (BV) of 49.37%, net protein utilization (NPU) of 42.33%, and protein digestibility-corrected amino acid score (PDCAAS) of 0.71. Comprehensive safety assessments included chemical contaminant screening, acute oral toxicity studies in rats and mice, in vitro chromosome aberration tests, and erythrocyte micronucleus tests. Heavy metals and aflatoxin B₁ levels were below regulatory limits. Acute oral toxicity studies established LD₅₀ values exceeding 10,000 mg/kg body weight in both rodent species, classifying this protein source as practically non-toxic. The 28-day sub-acute toxicity study showed no significant adverse effects at low doses (6.25% protein replacement). Both genotoxicity assays (mammalian cell chromosome aberration assay and mammalian erythrocyte micronucleus test) returned negative results. These findings establish R. eutropha H16-derived SCP as a safe, nutritious, and sustainable protein source with considerable potential for feed and food applications, contributing to global food security and environmental sustainability. Full article

Background: The growing demand for safe and effective phytopharmaceuticals underscores the importance of studying regionally available medicinal plants. Acorus calamus L. and Calendula officinalis L., widely distributed in the Republic of Kazakhstan, are promising sources of biologically active compounds with significant pharmacological potential. However, the combined use of their CO₂ extracts remains insufficiently characterised, particularly regarding possible synergistic interactions. Therefore, the development of new dosage forms and their comprehensive pharmacological and toxicological evaluation is a priority in modern pharmaceutical research. Methods: Concentrated extracts from Acorus calamus rhizomes and Calendula officinalis flowers were obtained using precritical CO₂ extraction. Safety was assessed through acute and chronic toxicity studies in laboratory animals according to standard non-clinical guidelines. Animals received graded doses of the extracts and developed formulations (‘Exkair’ tablets and ‘Zerp-Ak-Broncho’ granules). Clinical condition, mortality, body weight, and behaviour were monitored. Biochemical, haematological, and histopathological analyses were performed. Antitussive activity was evaluated in vivo by measuring oedema inhibition relative to reference drugs. Results: The CO₂ extracts and formulations demonstrated low toxicity and good tolerability, with no mortality or significant adverse effects observed even at high doses. Biochemical and haematological parameters remained within physiological ranges, and histopathological examination revealed no structural alterations in internal organs. Both ‘Exkair’ and ‘Zerp-Ak-Broncho’ exhibited pronounced antitussive activity, confirmed by significant suppression of oedema. This effect is likely associated with the synergistic action of flavonoids, terpenoids, and phenolic compounds. Conclusions: The findings indicate that CO₂ extracts of Acorus calamus L. and Calendula officinalis L., as well as the developed formulations, possess a favourable safety profile and significant antitussive activity. These results support their further development as phytotherapeutic agents in Kazakhstan. Full article

Quinazolinone derivatives are well-known anticancer agents; anticancer properties are also part of the broad spectrum of biological activity of coumarins. Conjugates containing quinazolin-4(3H)-one and coumarin fragments linked by polymethylene bridges of varying lengths were designed to improve properties of both parental compounds and create new anticancer or antibacterial agents. 3-{3-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]propyl}quinazolin-4(3H)-one was synthesized as the base compound. It demonstrated moderate cytotoxicity against leukemia (K562 and HL60) and neuroblastoma (SH-SY5Y) cells in vitro, combined with relatively low acute, subacute, and chronic toxicity in vivo. Conjugates with various substituents and linkers were then synthesized to evaluate the structure–activity relationship. A study of the synthesized compounds on cell cultures showed that the introduction of a methyl substituent into the benzene ring of the coumarin fragment led to both an increase in cytotoxicity and expansion of its spectrum of action. Testing of the hybrids against Gram-positive and Gram-negative bacteria revealed that the introduction of halogens into the quinazoline fragment in the compounds or the elongation of the linker led to the emergence of pronounced antibacterial properties, which were most clearly manifested against Acinetobacter baumanii. The possibility of directing activity of quinazoline-4(3H)-one–coumarin hybrids by varying the substituents and the length of the linker was shown. Full article

Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide analogs of the classical NSAIDs (NSI-1–NSI-9) were developed and synthesized to mask the carboxylic acid moiety and minimize COX-induced adverse effects while maintaining anticancer activity. The cytotoxic effect of such substances has been demonstrated in some leukemia cell lines (HL-60, MV4-11, KG1a, and K562). NSI-5 exerted the highest anti-leukemic activity among these sulindac analogs, as determined at a sub-micromolar level in all cell lines studied, by IC50. This mechanistic data also demonstrated that NSI-5 induced apoptosis that was dose-dependent, especially in HL-60 cell lines, and increased the sub-G1 cell fraction. This apoptotic process was also accompanied by a significant decrease in mitochondrial membrane potential, which is characteristic of the induction of the intrinsic apoptotic process. Interestingly, NSI-5 decreased the intracellular reactive oxygen species (ROS) and the expression of most antioxidants (catalase and glutathione synthetase), as well as the redox balance. Gene characterization in vitro also suggested activation of apoptotic pathways, where expression of Bax, Bak1, and Caspase-3 increased, suggesting a potential p53-independent apoptotic pathway, in contrast to control for Bcl-2 expression. Collectively, these findings indicate that NSI-5 is a promising in vitro anti-leukemic lead compound, with activity associated with mitochondrial dysfunction and altered redox regulation. The observed effects are consistent with previously reported COX-independent activity of structurally related NSAID derivatives, and support further investigation of NSI-5 in preclinical models. Full article

The active constituents of essential plant oils (EOAIs), monoterpenoid carvacrol and monoterpene p-cymene, are widely distributed in many aromatic plants and their products. They differ in that carvacrol has a phenolic functional group. The numerous pharmacological effects of these two EOAIs are well known. In different doses/concentrations, they exhibit analgesic, neuroprotective, vasorelaxant, anti-inflammatory, antiviral, antibacterial and antiparasitic effects. The acute toxicity of carvacrol and p-cymene in rats and the free-living nematode Caenorhabditis elegans was investigated. Furthermore, the impact of subacute administration of these two terpenes on general health, CNS integration, i.e., motor coordination and balance of rats, as well as their effects on the movement of adult C. elegans, was also examined. The aim was to compare the effects and describe in more detail the selective toxicity of carvacrol and p-cymene. The calculated LD₅₀ value of carvacrol was 790.15 ± 1.15 mg/kg, while the LD₅₀ value of p-cymene is above 3000 mg/kg. Tested doses of carvacrol and p-cymene administered for 28 days (50, 100, and 200 mg/kg) did not exert any effect on the CNS of rats or cause any clinical disorders. LC₅₀ value of carvacrol for adult C. elegans was 184.13 ± 1.51 μM and for p-cymene 1268 ± 1.65 μM. In subacute testing, carvacrol showed negative effects on C. elegans reproduction, distance traveled, movement speed and rotational index at lower concentrations than p-cymene, indicating higher toxicity, which may be due to its phenolic structure. On the other hand, although less toxic to C. elegans, p-cymene exhibited a specific effect on worm motility, with more rolling which should be further investigated, and can be a consequence of cuticle damage or loss of orientation. Full article

Fluorescent dyes are commonly used as tracers in hydrological investigations to quantify transport pathways, residence times, mixing behavior, and connectivity in surface water, groundwater, and coastal systems. Despite their long history of application, the ecological implications of deliberate dye releases are not well understood. This review synthesizes current knowledge on the physico-chemical characteristics, environmental behavior, and ecotoxicological effects of major dye classes, with emphasis on rhodamines, fluorescein derivatives, and sulfonated xanthene dyes commonly used in water tracing studies. Toxicity data for algae, cyanobacteria, invertebrates, and fish show large inter-specific variability. Some dyes, particularly rhodamine B and eosin Y, show acute or sub-lethal effects at concentrations detected during poorly controlled applications. By contrast, dyes with high polarity and extensive sulfonation (e.g., rhodamine WT, sulforhodamine B, pyranine, and fluorescein) show consistently low toxicity and minimal bioaccumulation potential. Environmental fate processes, including photolysis, sorption, and transformation into potentially more reactive products, influence exposure dynamics, especially in clear, shallow, or slow-moving systems. This review also evaluates regulatory frameworks and operational guidance for safe use, identifies gaps in toxicological and fate data, and proposes recommendations for minimizing environmental impact through dye selection, mass optimization, injection design, and monitoring. The findings support the continued use of fluorescent dyes but highlight the need for more systematic assessment of transformation products, chronic and sub-lethal responses, and cumulative exposure in sensitive environments. Full article

Radioligand therapy (RLT) offers the ability to deliver radiation to specific cells based on the presence of certain targets. RLT with [¹⁷⁷Lu]Lu-DOTATATE was approved in 2018 by the US Food and Drug Administration (FDA) for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). As RLT has become integrated into clinical practice, understanding the presence of and management strategies associated with acute, subacute, or delayed toxicities is essential to optimize patient outcomes. In this review article, we consider the risk factors for complications and any preventative strategies that may be employed. We present an overview of the toxicities that could occur during or soon after RLT infusion and discuss recommended management strategies, both from the literature and from experience in the clinical administration of RLT for patients with GEP-NETs. We highlight the importance of robust procedures for handling emergency situations and the potential for radioactive contamination from patients’ bodily fluids. Furthermore, the potential for delayed toxicities is also considered. In addition to toxicities and management, we also review the practical radiation safety precautions that are important both during and following RLT treatment. Full article

Dromedary camels possess unique anatomical, physiological, and metabolic adaptations that enable survival in arid environments; however, these same adaptations make them highly sensitive to nutritional imbalance under modern feeding conditions. This review synthesizes current knowledge on nutritional pathologies and metabolic disorders in camels, emphasizing the links between diet composition, foregut fermentation, mineral status, and systemic health. Imbalances in energy and carbohydrates predispose camels to subacute and acute acidosis, negative energy balance, and ketosis-like syndromes, particularly when rapidly fermentable feeds are introduced without adequate fiber or water. Protein and nitrogen disorders, including ammonia toxicity and impaired urea recycling, arise from mismatches between degradable protein, fermentable energy, hydration, and mineral availability. Widespread deficiencies of phosphorus, copper, cobalt, zinc, selenium, and vitamins A and E remain major constraints, leading to pica, poor microbial fermentation, oxidative stress, immunosuppression, reproductive failure, and skeletal disorders. Nutritional disturbances frequently extend beyond the gastrointestinal tract, forming a gut–liver–kidney metabolic axis characterized by hepatic dysfunction, renal compromise, and systemic oxidative stress. The review also addresses gastrointestinal impaction, foreign-body ingestion, toxic plant consumption, and feeding on human food waste as emerging nutritional challenges, particularly in peri-urban systems. Advances in diagnostic ultrasonography, feed evaluation techniques, probiotics, mineral–vitamin supplementation, and omics-based approaches are discussed as tools for improving early diagnosis and precision nutrition. Despite growing research interest, the lack of camel-specific feeding standards and reliance on cattle-based recommendations remain critical gaps. This review highlights the need for species-specific nutrient requirement models, sustainable rangeland management, and integrative research to support the health, resilience, and productivity of camels under changing environmental and production systems. Full article

Chronic exposure to the cyanotoxin microcystin-LR is an emerging environmental driver of non-alcoholic fatty liver disease (NAFLD); however, the initiating molecular events at sub-lethal, environmentally relevant concentrations remain elusive. Current safety guidelines focus primarily on acute injury, potentially overlooking silent metabolic disruption. The present study investigates the early metabolic toxicity of chronic low-dose microcystin-LR (10 µg/L) in a 7-week rat model, specifically focusing on pre-symptomatic perturbations in lipid homeostasis. By integrating biochemical profiling with multivariate systems toxicology (LASSO and PLS-DA), we identified a specific phenotype of “Silent Hepatic Total Cholesterol Accumulation” (T-CHOL +16%, p = 0.01) occurring in the absence of systemic dyslipidemia or overt liver injury. Mechanistic analysis revealed a specific dual failure of cholesterol homeostasis, characterized by the paradoxical upregulation of the influx transporter Ldlr (LASSO coef +0.661) and the suppression of the efflux transporter Abcg1 (PLS1 loading −0.358). Crucially, Ldlr upregulation occurred despite the concomitant transcriptional downregulation of Srebp2 (Spearman ρ = −0.585), indicating a regulatory uncoupling mechanism. We propose that microcystin-LR-induced protein phosphatase 2A (PP2A) inhibition likely drives this uncoupling via a post-transcriptional override—possibly involving ERK/RSK-mediated Ldlr mRNA stabilization. Concurrently, this inhibition appears to block LXR-mediated Abcg1 expression through sustained AMPK hyperactivation resulting from the loss of dephosphorylation. These findings indicate liver-specific cholesterol accumulation as the critical first step of environmental NAFLD pathogenesis, suggesting that current WHO guidelines (1 µg/L) may require re-evaluation regarding metabolic safety. We propose the hepatic Ldlr/Abcg1 ratio as a potential early biomarker for revised risk assessment. Full article

Antiviral substances are considered emerging contaminants. Once released into the environment, they may affect organisms through complex and often still-unknown mechanisms. This study focuses on a class of antiviral substances with potential use in treating COVID-19 patients, aiming to identify specific structural characteristics that significantly contribute to their ecotoxicity. An empirical approach called quantitative structure–activity relationship (QSAR) was used for this purpose. The study examined 13 antiviral substances: atazanavir, daclatasvir, darunavir, emtricitabine, favipiravir, lopinavir, nirmatrelvir, oseltamivir, remdesivir, ribavirin, ritonavir, and sofosbuvir. The ecotoxicity of these antivirals was assessed using three tests: the Aliivibrio fischeri test, the Chlorella sp. test, and the Pseudomonas putida test. These three microorganisms represent different trophic levels in aquatic and soil ecosystems. Ecotoxicity was expressed as EC₂₀ and EC₅₀, and these values served as the dependent variables in the QSAR models. A large set of numerical descriptors calculated from the molecular structures of the antivirals was used as an independent variable. EC₂₀-based QSAR models offer insight into the effects of antivirals under sub-lethal exposure conditions. The results indicated that sub-lethal exposure in Aliivibrio fischeri was associated with favorable electronic properties and compact structures that promote cellular accumulation, while long-range fragments reduced toxicity. In Chlorella sp., sub-lethal exposure was driven by optimal molecular size, chain length, and specific electronic groups enabling cell penetration and biochemical inhibition. For sub-lethal exposure in P. putida, lipophilicity and reactive group geometry enhanced toxicity, while high short-range polarity mitigated it by limiting membrane permeability. Acute toxicity patterns showed similar trade-offs: strong electronic reactivity increased potency, but steric bulk, long-range polarity, or unfavorable mass distribution frequently restricted bioavailability and reduced toxic effects. Overall, the models demonstrated that antiviral toxicity results from a balance of electronic activity, structural accessibility, and physicochemical constraints, providing a mechanistic basis for predicting the environmental risk of selected antiviral substances. Full article

Fine particulate matter (PM2.5)-induced ovarian damage has attracted widespread attention, but differences in cytotoxicity and underlying mechanisms of water-soluble (WS-PM2.5) and water-insoluble (WIS-PM2.5) fractions are unclear. To investigate potential effects of PM2.5 from livestock farming environments on animal ovaries, PM2.5 samples were collected from large-scale cattle barns. There were significant differences between fractions regarding elemental composition, proportion of water-soluble ions, polycyclic aromatic hydrocarbon content, and endotoxin concentrations. Based on transcriptome sequencing results, in a cowshed PM2.5 exposure model (rats), differentially expressed ovarian mRNAs were significantly enriched in signaling pathways such as cytokine interaction and the Hippo pathway, with the expression of thioredoxin-interacting protein (Txnip) significantly increased. In vitro (primary rat ovarian granulosa cells), short-term exposure to WS-PM2.5 (12 h) significantly induced inflammatory factor release, acute oxidative stress, mitochondrial dysfunction, and intracellular Ca²⁺ overload, with characteristics of rapid acute injury. However, extended (24 h) WIS-PM2.5 exposure had greater disruptive effects on estrogen homeostasis, intracellular enzyme release (LDH), and mitochondrial structure (subacute characteristics). Furthermore, downregulating Txnip expression via inhibitors effectively mitigated cowshed PM2.5-induced ovarian granulosa cell toxicity, oxidative stress, and mitochondrial and hormonal dysfunction. In summary, solubility of cowshed PM2.5 components affected cytotoxic characteristics, and Txnip was a key factor linking oxidative stress to granulosa cell damage. The study provided a mechanistic basis and potential targets for preventing and controlling PM2.5-induced ovarian damage in livestock environments. Full article

Plantain (Musa paradisiaca L.) is a tropical monocotyledonous, succulent plant of the Musaceae family commonly grown for food in the tropical regions of the African, Asian, and South American continents, where its parts are also sought for ethnomedicinal purposes in the treatment of burns, inflammation, and diabetes, among others. In the present preliminary exploratory study, the ethanol extract of the underutilized Musa paradisiaca peel (MPE) was evaluated for its in vitro inhibitory effects on α-amylase and α-glucosidase, as well as its in vivo hypoglycemic activity and potential biochemical toxicity. MPE (100, 200, 400 mg/kg) was orally administered to normal experimental rats for 30 days, following which the lipid profile, antioxidant status, and serum/tissue indices of hepatic, renal, and cardiac functions were evaluated. MPE produced significant inhibition (p < 0.05) of α-amylase (37%) and α-glucosidase (46%) at 120 µg/mL in vitro. The effect was lower than that of acarbose (IC₅₀ = 44.4 ± 1.14 and 15.60 ± 0.01 µg/mL, respectively). A modest blood glucose-lowering effect of MPE was observed at the highest tested dose (400 mg/kg) following subacute oral administration. During this treatment period, no biochemical alterations of toxicological importance were caused by MPE, as the organ–body weight ratio and serum/tissue indicators of organ function/damage were not adversely altered. In conclusion, MPE demonstrated inhibitory activity against both α-amylase and α-glucosidase, which may contribute to its potential hypoglycemic effects. Additionally, the findings indicate that the peel extract is non-toxic in rats following sub-acute administration at doses up to 400 mg/kg body weight. Further studies involving diabetic models and chronic exposure will substantiate and extend these preliminary observations. Full article

Rapid evaluation of water toxicity requires biological methods capable of detecting sub-lethal physiological changes without depending on chemical identification. Conventional microscopy-based bioassays are limited by low throughput and difficulties in observing small, transparent and fast-moving microorganisms. This study applies a laser-biospeckle, non-imaging microbioassay to assess the motility responses of Paramecium caudatum and Euglena gracilis exposed to two organic pollutants, trichloroacetic acid (TCAA) and acephate. Dynamic speckle patterns were recorded using a 638 nm laser diode (Thorlabs Inc., Tokyo, Japan) and a CCD camera (Gazo Co., Ltd., Tokyo, Japan) at 60 fps for 120 s. Correlation time, derived from temporal cross-correlation analysis, served as a quantitative indicator of motility. Exposure to TCAA (0.1–50 mg/L) produced strong concentration-dependent inhibition, with correlation time increasing up to 16-fold at 500× PL in P. caudatum (p < 0.01), whereas E. gracilis showed a delayed response, with significant inhibition only above 250× PL. In contrast, acephate exposure (0.036–3.6 mg/L) induced motility enhancement in both species, reflected by decreases in correlation time of up to 57% in P. caudatum and 40% in E. gracilis at 100× PL. Acute trends diminished after 24–48 h, indicating time-dependent physiological adaptation. These results demonstrate that biospeckled-derived correlation time sensitively captures both inhibitory and stimulatory behavioral responses, enabling real-time, high-throughput water toxicity screening without microscopic imaging. The method shows strong potential for integration into automated water-quality monitoring systems. Full article

There is a critical gap in the preclinical research of recombinant human interferons (rhIFNα-2b and rhIFN-γ), as most studies focus on modified variants, which complicates the understanding of the native molecules’ properties. This study addresses this limitation by comprehensively evaluating the structural stability and intrinsic toxicity of purified IFNs. Our findings confirm that both interferons retain their bioactivity (antiviral, antiproliferative, and immunomodulatory) and exhibit remarkable stability under controlled conditions. Accelerated stability assays showed that neither protein lost biological potency after 18 days at various temperatures, supporting their potential as liquid formulations. Acute and sub-chronic toxicity studies in rodent, non-rodent, and higher-organism animal models showed no signs of toxicity, even at doses 100 to 300 times higher than therapeutic levels. These assays, combined with the absence of pyrogens, support a favorable safety profile for clinical use, with no evidence of systemic or structural damage. This work establishes a reproducible experimental model and lays the groundwork for future preclinical evaluations. We underscore the importance of characterizing the safety profile of active pharmaceutical ingredients from the earliest stages of biopharmaceutical development to ensure a safe and well-founded transition to human clinical trials. Furthermore, these results open the door for the development of advanced formulations and alternative routes of administration, such as the intranasal route, an area with significant potential. Full article

Objectives: One of the major trends in modern computational toxicology is the development of explainable predictive tools. However, the complex nature of the mechanistic representation of biological organisms and the lack of relevant data remain limiting factors. Methods: This work provides a publicly available dataset of 12,654 compounds with mouse intravenous ${\mathrm{LD}}_{50}$ values, as well as docking scores (Vina-GPU 2.0) against 44 toxicity-associated proteins. NIH and Brenk filters were applied to refine the chemical space. Results: Across the entire protein panel, the human ether-a-go-go–related gene channel (hERG/KCNH2), vasopressin receptor 1A (AVPR1A), the L-type voltage-gated calcium channel Cav1.2 (CACNA1C), the potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) and endothelin receptor A (EDNRA) showed the strongest association with acute toxicity. Statistically significant differences were found in the distribution of ${\mathrm{LD}}_{50}$ values for compounds that bind antitargets compared with non-binders. Using known bioactive molecules such as anisodamine, butaperazine, soman, and several cannabinoids as examples confirmed the effectiveness of inverse docking for elucidating mechanism of action. Conclusions: The dataset offers a resource to advance transparent, mechanism-aware toxicity modeling. The data is openly available. Full article