Poisoning Research Articles

Advanced LC-MS/MS Technique for Environmental Ivermectin Detection.

Ivermectin is a widely used broad-spectrum antiparasitic agent employed in both companion animals and livestock. While generally safe for mammals, its acute and chronic toxicity has been proven in many nontarget fish and insect species at low concentrations. The present study aimed to develop, validate, and test a more accurate method for ivermectin detection in various matrices (feces, soil, and sewage) for environmental studies. The method was validated using the Eurachem network. The applicability of the method was established at 1.5-500 μg/L for feces and 1.5-15 μg/L for sewage and soil. No dilution effect was observed at 5000 μg/L. The limit of detection was 0.66, 0.54, and 0.36 μg/kg for feces, soil, and sewage, respectively. The limit of quantification was set at 1.5 μg/kg and verified experimentally. Overall recovery was 92.27 ± 12.01% for feces and 96.19 ± 13.78% in soil, reaching a linearity of at least 0.99. The present method was successfully applied to 228 feces, 20 sewage, and 105 soil samples. This validated method enables the precise detection and quantification of ivermectin in the tested matrices, thereby envisaging potential applications in environmental monitoring studies with improved sensitivity and specificity.

Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B.

Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with "epidrugs" is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4 , lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.

Sustainable bioenergy potential of peat-moss derived hydrothermal aqueous phase: Insights into methane production and organic transformation

Achieving Sustainable Development Goal 7 (SDG-7) by exploring bioenergy production from peat-moss derived hydrothermal aqueous phase (HAPs) through anaerobic digestion (AD). This study investigated six combinations of hydrothermal conversion temperature (HCT) and residence time (HCRT). Methane yields varied significantly, with the highest (256 mL/g COD) achieved at 200 °C:4h, while the lowest (97 mL/g COD) was at 320 °C:4h due to formation of toxic and refractory organics. Microtox analysis showed acute toxicity > 98 % for all HAPs. Notably, higher HCT and HCRT led to more complex and diverse organic patterns, promoting the formation of humus-like substances, ester, alkane alcohols, and aromatics. GC–MS analysis revealed a 23 % increase in aldehyde and ketone compounds at 320 °C:4h. Continuous experiments confirmed 29 % COD removal efficiency at 320 °C:4h and identified 13 refractory organics, highlighting challenges in biodegradability. These findings provided valuable insights for optimizing AD processes, enhancing bioenergy production, and advancing sustainable energy solutions in alignment with SDG-7.

In-situ and ex-situ preparation of Bi2S3 on the BiVO4/TiO2 to construct Bi2S3/BiVO4/TiO2 heterojunction for efficient Cr(VI) reduction

The environmentally friendly and rapid removal of hexavalent chromium (Cr(VI)) from wastewater has garnered significant attention, driven by the severe acute toxicity and carcinogenic properties associated with Cr(VI). The design and synthesis of heterojunctions are recognized as effective solutions for enhancing the photocatalytic performance of TiO2 based materials. BiVO4/TiO2 and Bi2S3/BiVO4/TiO2 composite films (BVT) were prepared via a simple hydrothermal method. The influence of Bi2S3 preparation methods (In-situ and Ex-situ) on the morphology, structure and properties of BVT was studied. The relative crystallinity of TiO2, BiVO4/TiO2, BVT(In-situ) and BVT(Ex-situ) were 50 %, 62 %, 72 % and 92 %, respectively. SEM shows that the morphology of Bi2S3 in BVT(In-situ) was nanoribbon and that of Bi2S3 in BVT(Ex-situ) was radioactive sphere. Compared with pure TiO2 and BiVO4/TiO2, the light absorption range of BVT composite material has been expanded from the ultraviolet light region to the visible region, the bandgap has been significantly narrowed, and the photocurrent density has been increased. The BVT(In-situ) shows stronger photoelectrical performance and reduction efficiency of Cr (VI) compared to BVT(Ex-situ), reaching 93.9 %. The photocatalytic reaction rate of BVT(In-situ) and BVT(Ex-situ) are 0.0291 min−1 and 0.0266 min−1, respectively. Density functional theory (DFT) calculations indicate that the work function of BiVO4 is higher than that of Bi2S3, and electrons will transfer from Bi2S3 to BiVO4 at the heterojunction interface. The BVT(In-situ) heterojunction constructed in this experiment greatly improves the separation and transport efficiency of photo-generated carriers, laying the foundation for the wide application of BVT heterojunction in the field of optoelectronics and providing a strategy for photocatalytic reduction of Cr(VI). The BVT(In-situ) with FTO conductive glass, it also can be applied to photovoltaic fields such as solar cells, photocatalysis and photodetectors.

Immunotropic Activity and Acute Toxicity of Melanin Isolated from Horse Chestnut (Aesculus hippocastanum L.) Seed Coats

Immunotropic Activity and Acute Toxicity of Melanin Isolated from Horse Chestnut (Aesculus hippocastanum L.) Seed Coats

Inhibitory potential of 7-hydroxycoumarin-3-carboxylic acid against tyrosinase and its effect on the preservation of fresh-sliced apples

Excessive tyrosinase expression leads to pigmented diseases in humans and browning in plants, necessitating effective tyrosinase inhibitors. This study investigated the inhibitory effect and mechanism of 7-hydroxycoumarin-3-carboxylic acid (7-HC-3-CA) on tyrosinase. Using UV–visible absorption spectroscopy, we found that 7-HC-3-CA effectively inhibited tyrosinase activity, with an IC50 value of 364 ± 1.3 μM. Enzyme kinetics, fluorescence methods and molecular simulation techniques revealed that 7-HC-3-CA acted as a reversible and competitive inhibitor, forming a stable complex with tyrosinase through hydrophobic interactions and hydrogen bonding. This altered the microenvironment of Tyr and Trp residues, causing the structural stretching and conformational changes that diminish catalytic activity.Preservation experiments demonstrated that 0.5 mM 7-HC-3-CA significantly reduced mass loss and decreased browning of fresh-sliced apples. It also lowered polyphenol oxidase activity from 0.22 to 0.18 and delayed phenolic oxidation, enhancing total phenolic content from 0.34 to 0.54, thereby controlling browning and extending storage life. Cell assays indicated that 0.5 mM 7-HC-3-CA had no significant impact on cell proliferation, with viability over 80 %. Acute toxicity tests proved that 0.5 mM of 7-HC-3-CA is completely non-lethal to KM mice. In conclusion, this study confirmed 7-HC-3-CA was a viable and safe antibrowning agent and revealed its potential application in the field of food preservation.

Evaluation of acute and subacute dermal toxicity of antibacterial bioactive glass-infused surgical cotton gauze in Wistar rats

Mesoporous bioactive glass, with its versatile characteristics and morphology, holds significant potential as an ideal hemostatic material. However, limited data is available regarding its toxicity levels. Consequently, this research intends to assess the acute and repeated dose dermal toxicity of Mesoporous antibacterial bioactive glass microsphere impregnated nonwoven surgical cotton gauze (MABGmscg) dressing in albino Wistar rats, following the standards set by the Organization for Economic Cooperation and Development. In the acute dermal toxicity study, the impact of MABG (@2000mg/kg BW) mscg dressing was assessed following a single dermal application in both male and female Wistar rats (n = 10). Mortality, clinical signs, body weight fluctuations and gross observations were consistently monitored over a14 day period following the single dose. The results indicated that, MABG (@2000mg/kg BW) mscg dressing upon dermal exposure did not cause any adverse effect in acute dermal toxicity study in Wistar rats compared to control group. Given that 2000 mg/kg BW of MABG was deemed a nontoxic dose, a repeated dose dermal toxicity study of MABGmscg dressing was subsequently conducted at three dose levels (@200, 500, 1000 mg/kg BW) over 28 consecutive days in Wistar rats. During the study period, no unscheduled deaths occurred, and there were no clinical signs associated with treatment, body weight variations or abnormal gross findings at necropsy in any groups. The analysis concluded that, MABGmscg dressing is safe to be considered as a hemostatic dressing at the various tested dose levels in Wistar rats.

Acute amiodarone-induced pulmonary toxicity in adult ICU patients with new-onset atrial fibrillation-A systematic review.

New-onset atrial fibrillation or flutter (NOAF) is a common arrhythmia in adult intensive care unit (ICU) patients. Intravenous amiodarone is one of the most used anti-arrhythmic drugs, despite its risk of inducing acute amiodarone-induced pulmonary toxicity (APT). We aimed to outline the body of evidence on acute APT in ICU patients with NOAF. We performed a systematic search using the population, intervention, comparison, and outcome (PICO) approach. We included studies of adults admitted to the ICU, who developed NOAF during their ICU stay, were treated with amiodarone, and reported on acute APT, irrespective of research design. The CASE guidelines were applied to evaluate the quality of the included studies, and study results are reported in accordance with the preferred reporting items for systematic reviews and meta-analyses. No randomised controlled trials or observational studies were identified. Nine case reports and one retrospective case series of fatal outcomes in ICU patients treated with amiodarone for NOAF constituted the evidence base. The quality of the included studies was high with a mean of 10 (range 8-12) of the 13 CASE guideline criteria fulfilled. The studies included a total of 16 critically ill adults who was diagnosed with acute APT after a mean of 9 days (range 2-20 days) following initiation of amiodarone with a mean total dose of amiodarone of 4553 mg (range 1100-13,500 mg) predominantly administrated intravenously. Three out of nine patients in the case reports died in the ICU during the amiodarone treatment. No long-term follow-up was conducted for the survivors. Acute APT in adult ICU patients treated with amiodarone for NOAF is poorly described and is based on a total of 16 reported cases. Additional studies assessing the safety of amiodarone in critically ill adults with NOAF in the ICU is warranted.

A study on the effectiveness of (+)-usnic acid as oral toxic sugar bait against adult male and female Anopheles gambiae

BackgroundDespite the application of various tools for the control of vectors of Plasmodium falciparum, malaria remains the major killer disease in sub-Saharan Africa accounting for up to 90% of deaths due to the disease. Due to limitations of the useage of chemical insecticides such as resistance, negative impact on the environment and to nontarget organisms, the World Health Organization (WHO) requires that affected countries find alternative vector control tools. This study evaluated the effectiveness of ( +)-usnic acid (UA) as an insecticide through oral administration to male and female Anopheles gambiae as an alternative or additional active ingredient to be used in toxic sugar bait.Methods( +)-usnic acid was diluted using acetone at 5, 10, and 15 mg/ml concentrations in three replicates. A 5 ml mixture of 2% food dye and 10% sugar using chlorine-free water mixed with the dilutions of the ( +)-usnic acid and negative control was made containing 2% food dye and 10% sugar solution. The preparations were soaked on a ball of cotton wool and placed over the net of a cup. 5 male and 5 non-blood-fed female newly hatched starved An. gambiae Kisumu strain were introduced together into a cup and monitored for knockdown and mortalities after 4, 24 48, and 72 h. The data were analysed using a multiple linear regression model using the lm function, a base R function and a posthoc test were conducted on the significant main effects and interaction terms using the emmeans function from the emmeans R package. All analyses were performed in RStudio using base R (version 4.3.3).ResultsThere was high mortality of both male and female An. gambiae after ingestion of the toxic sugar bait. 15 mg/ml usnic acid caused the highest mortality (50%) within the first 4 h compared to 5 and 10 mg/ml ( +)-UA. There was a decline in the mortality rate with increased exposure time from 24 to 72 h, however, there was a significant difference in mortality at 5, 10 and 15 mg/ml. Acute toxicity was associated with ingestion of 15 mg/ml after 24 h. 72 h post-mortality was lower in all concentrations than in the control. High mortality was observed among females over the first 4 h (60%) compared to males (40%) due to higher feeding rate of the toxic agent. The proportion of dead males and females was equal after 24 h while after 48 h, the proportion of dead males was high.There was a significantly lower mortality rate after 72 h for both males and females (0 to 13.3%). Compared to all the treatments, high mortality of males was observed.ConclusionsThe results of this study indicate that ( +)-UA when administered as oral sugar bait to An. gambiae has insecticidal properties and is a suitable ingredient to be used as a toxic agent in the novel attractive toxic sugar bait for the control of malaria vectors. ( +)-UA may be an alternative active ingredient as toxic bait in the effort to reduce and eliminate the transmission of Plasmodium falciparum in Africa.

Therapeutic strategies for mobile spine chordoma: en bloc Versus intralesional surgery with adjuvant charged-particle therapy.

The aim of this retrospective study is to analyze the impact of en bloc resection with negative margins versus intralesional resection plus adjuvant hadron-therapy (HT) on local control (LC) and overall survival (OS) in patients with mobile spine chordomas. Mechanical complications incidence as well as risk factors, and outcome differences are investigated as secondary endpoints. 33 patients in a period from January 2013 to December 2021 were enrolled for the final analysis. The inclusion criteria were: lesions located in the mobile spine (C1-L5), age ≥ 15 years, minimum follow-up of 2 years, en bloc or intralesional surgical resection, virgin or recurrent chordomas, with only one previous surgical treatment. No difference was found in terms of LC between the two groups. The presence of pathologic fracture at pre-operative imaging and the presence of macroscopic residual tumor after surgery, independently from its entity, seemed to be associated with an increased risk of LR. No difference was found between planned en bloc and planned intralesional surgery in terms of mechanical complications occurrence. Eight patients (24.24%) had mechanical complications during the follow up period: male sex, presence of pathologic fracture at baseline, a combined surgical approach, the use of carbon fiber-only hardware appeared to be associated with an increased risk of mechanical complications after the primary surgery. En bloc resection, whenever possible, is always to be preferred for its widely recognized potential in LC and OS improvement. However, technology advances in high-dose conformal charged-particle therapy have allowed improvement of local control rates as an adjuvant therapy of intralesional surgery for mobile spine chordoma, with acceptable acute and chronic toxicity.

The Role of Oral Nutritional Supplements in Head and Neck Cancer Patients Undergoing Chemoradiotherapy.

This study aimed to assess the impact of oral nutritional supplements (ONS) on nutritional intake, body weight, and body composition in head and neck cancer (HNC) patients undergoing chemoradiotherapy. The study evaluated whether ONS could prevent treatment-related nutritional deterioration. This prospective observational pilot study included 30 HNC patients randomized into two groups: ONS (n = 15) and No ONS (n = 15). All participants underwent chemoradiotherapy, with the ONS group receiving 200 mL of a high-calorie, high-protein supplement twice daily. Nutritional status, including body weight, BMI, fat mass, fat-free mass, and bone mass, was assessed at three time points: baseline, mid-treatment, and end of treatment. Data were analyzed using the Mann-Whitney U test, with a p-value of ≤0.05 considered statistically significant. At baseline, there were no significant differences between the two groups in body weight, BMI, or body composition. By the end of radiotherapy, the No ONS group showed significant reductions in body weight (p < 0.001), BMI (p < 0.001), fat mass (p < 0.001), and fat-free mass (p < 0.001), while the ONS group maintained more stable nutritional parameters. Acute radiotherapy toxicities, including nausea, dysphagia, and oral mucositis, were not significantly different between the two groups. ONS effectively mitigates weight loss and preserves body composition in HNC patients undergoing chemoradiotherapy. While no significant reduction in radiation-induced toxicities was observed, the nutritional benefits of ONS support its use in preventing malnutrition in this patient population. Larger studies are needed to further validate these findings.

Ir(III) Diamine Transfer Hydrogenation Catalysts in Cancer Cells

AbstractThe development of catalytic metallodrugs is an emerging field that may offer new approaches to cancer chemotherapeutic design. By exploiting the unique properties of transition metal complexes, in‐cell catalysis can be applied to modulate the cellular redox balance as part of a multi‐targeting mechanism of action. We describe the synthesis and characterization of six coordinatively unsaturated iridium(III) diamine catalysts that are stable at physiological pH in aqueous solution. Reduction of the colorimetric substrate 2,6‐dichlorophenolindophenol by transfer hydrogenation under biologically compatible conditions achieved turnover frequencies up to 63 ± 2 h−1 and demonstrated that the source of hydride (sodium formate) is the limiting reagent, despite being in a 1000‐fold excess of the catalyst. The catalyst showed low in vivo acute toxicity in zebrafish embryos and modest in vitro potency towards cancer cells. When administered alone, the catalyst generated oxidative stress in cells (an effect that was conserved in vivo), but co‐treatment with a nontoxic dose of sodium formate negated this effect. Co‐treatment with sodium formate significantly enhanced catalyst potency in cancer cells (A2780 ovarian and MCF7 breast cancer cells) and drug‐resistant cells (A2780cis and MCF7‐TAMR1) but not in non‐tumorigenic cells (MRC5), demonstrating that a redox‐targeting mechanism may generate selectivity for cancer cells.

Clinico-Epidemiological Profile and Outcome of Acute Poisoning Patients admitted to Intensive Care Unit in A Tertiary Level Private Hospital in Bangladesh

Background: Acute poisoning is a prevalent health issue necessitating Intensive Care Unit (ICU) admission in developing countries. This study evaluates the socio-demographic characteristics, clinical parameters, and outcomes of acute poisoning patients admitted to the ICU in a tertiary level private hospital in Bangladesh. Method: This retrospective cohort study was conducted at tertiary care private hospital in Narayanganj, Bangladesh. Data was collected from ICU medical records from January 2023 to April 2024, enrolling a total of 57 patients aged 18 years or more who presented with acute poisoning. Data analysis was performed using Stata (Statistical Software for Data Science) 17.0(p &lt; 0.05) Results: Out of 57 patients, 52.63% were females, with mean age of 27.84 years. Suicidal intent accounted for 84.21% of cases, and the primary reasons for poisoning included marital (61.40%) and familial disharmony (15.79%). The predominant type of poisoning was due to sedatives (17.54%) followed by aluminium phosphide (14.04%), and stupefying agents (14.04%). Aluminium phosphide poisoning had a 100% fatality rate, while sedatives and several other agents had 100% recovery rate. Statistical analysis showed a significant association between the type of poison and the final outcome (χ2(15) = 38.7996, p = 0.001). Conclusion: The study highlights the prevalence of intentional poisoning among young adults, especially females, with sedatives, aluminium phosphide, and stupefying agents being the most common. The high mortality rate from aluminium phosphide underscores the need for strict regulations and public awareness to control access to these substances. Bangladesh Crit Care J September 2024; 12 (2): 89-95

Tri-iso-butyl phosphate (TiBP) exposure induces neurotoxicity by triggering oxidative stress accompanied by neurotransmitter system disruptions and apoptosis in zebrafish larvae

The current research sheds light on the biological toxicity of organophosphate flame retardants (OPFRs), yet it overlooks the neurotoxicity and potential molecular mechanisms of tris(1,3-dichloro-2-propyl) phosphate (TiBP), a prominent constituent of the OPFRs. To address this, we utilized zebrafish larvae as a model to investigate TiBP's acute toxicity and neurotoxic effects, along with the associated molecular pathways. Our findings revealed that the 96 h and 120 h LC50 values for TiBP were 56.51 mg/L and 48.85 mg/L, respectively. Gradient exposure based on the 120 h LC50 demonstrated that TiBP induced developmental toxicity, characterized by elevated heart rate, reduced body length, and diminished eye distance. Additionally, a decrease in swimming activity was observed in the light test, along with the inhibition of the neuro crest cell development in Tg (HuC:eGFP) and Tg (sox10: eGFP) zebrafish larvae following TiBP exposure, as well as the alterations of neurogenesis and ACh-related genes. Expression of key neurodevelopment genes, including mbpa, gap43, nestin, ngfra, was significantly downregulated. Furthermore, heightened anxiety-like behaviors in open field and phototaxis tests were observed, concomitant with neurotransmitter imbalances. Specifically, there was an increase in DA levels, a decrease in GABA, and an upregulation of AChE activity. These disruptions were primarily mediated through transcriptional dysregulation of neurotransmitter synthesis, transport, and reception. Upon exposure to TiBP, zebrafish larvae exhibited a concentration-dependent increase in both ROS level and apoptosis. An upregulation of antioxidant enzymes and their transcription levels indicated the presence of oxidative stress in the larvae. The induction of ddit3 was congruent with the observed apoptosis, suggesting that it may be triggered by oxidative stress via the ERs-CHOP pathway. In summary, our study indicates that oxidative stress is a pivotal molecular event in the neurotoxicity induced by TiBP, implicating the disruption of the GABAergic, dopaminergic, and cholinergic systems, as well as triggering apoptosis.

Investigation of serum biochemical responses in White Leghorn layer birds following acute avian toxicity screening using indoxacarb

The experiment was undertaken to study the effect of indoxacarb on various biochemical parameters in White Leghorn layer birds for a period of 14 days following a single oral administration. The study follows OECD guideline no. 223. White Leghorn layer birds (n=30) weighing between 1.2 to 1.6 kg were used for the study. Six birds were kept as the control group and approximately 2 ml of blood was collected in EDTA tubes on days 7 and 14 of the experiment. Biochemical parameters such as alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine and blood urea nitrogen (BUN) were estimated. The mean values of ALP, AST, ALT and BUN were found significantly higher on days 7 and 14 of the acute toxicity study of indoxacarb in layers as compared to that of the control group. Keywords: Biochemical, layers, indoxacarb

Family Malvaceae: a potential source of secondary metabolites with chemopreventive and anticancer activities supported with in silico pharmacokinetic and pharmacodynamic profiles.

Cancer is the second most widespread cause of mortality following cardiovascular disorders, and it imposes a heavy global burden. Nowadays, herbal nutraceutical products with a plethora of bioactive metabolites represent a foundation stone for the development of promising chemopreventive and anticancer agents. Certain members of the family Malvaceae have traditionally been employed to relieve tumors. The literature concerning the chemopreventive and anticancer effects of the plant species along with the isolated cytotoxic phytometabolites was reviewed. Based on the findings, comprehensive computational modelling studies were performed to explore the pharmacokinetic and pharmacodynamic profiles of the reported cytotoxic metabolites to present basis for future plant-based anticancer drug discovery. All the available information about the anticancer research in family Malvaceae and its cytotoxic phytometabolites were retrieved from official sources. Extensive search was carried out using the keywords Malvaceae, cancer, cytotoxicity, mechanism and signalling pathway. Pharmacokinetic study was performed on the cytotoxic metabolites using SWISS ADME model. Acute oral toxicity expressed as median lethal dose (LD50) was predicted using Pro Tox 3.0 web tool. The compounds were docked using AutoDock Vina platform against epidermal growth factor receptor (EGFR kinase enzyme) obtained from the Protein Data Bank. Molecular dynamic simulations and MMGBSA calculations were performed using GROMACS 2024.2 and gmx_MMPBSA tool v1.5.2. One hundred forty-five articles were eligible in the study. Several tested compounds showed safe pharmacokinetic properties. Also, the molecular docking study showed that the bioactive metabolites possessed agreeable binding affinities to EGFR kinase enzyme. Tiliroside (25), boehmenan (30), boehmenan H (31), and isoquercetin (22) elicited the highest binding affinity toward the enzyme with a score of -10.4, -10.4, -10.2 and -10.1Kcal/mol compared to the reference drug erlotinib having a binding score equal to -9Kcal/mol. Additionally, compounds 25 and 31 elicited binding free energies equal to -42.17 and -42.68Kcal/mol, respectively, comparable to erlotinib. Overall, the current study presents helpful insights into the pharmacokinetic and pharmacodynamic properties of the reported cytotoxic metabolites belonging to family Malvaceae members. The molecular docking and dynamic simulations results intensify the roles of secondary metabolites from medicinal plants in fighting cancer.

MQ232, A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases

Background: Vaptans were developed at the end of the previous century as V2R antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and the autosomal polycystic kidney disease (ADPKD). However, its use is not as widespread as it should be due to price issues, a narrow therapeutic window and some side effects. With the aim of discovering new efficient and safer V2R antagonists, we screened animal venoms and identified several interesting peptide toxins. Among them, MQ1 displayed such unique biological properties in that regard that it was the starting point for the development of a potential drug candidate. Methods: Human T-cell assays and bioinformatics was used to mitigate MQ1 immunogenicity risk. The MQ232 biodistribution in mice was done by positron emission tomography (PET). Pharmacodynamics, pharmacokinetics, acute and chronic toxicity tests were performed on control rats. A rat experimental model of dDAVP-induced hyponatremia, an ex vivo mice model of renal cysts and a mice orthologous model of ADPKD were used to validate MQ232 efficacy in these pathologies. Results: Three mutations were introduced in MQ1 to mitigate its immunogenicity risk. A fourth gain-of-function mutation was added to generate MQ232. MQ232’s safety was demonstrated by a first toxic dose as high as 3,000 nmol/kg and a strong kidney organ selectivity by PET imaging, while showing almost no interaction with the liver. MQ232’s efficacy was first demonstrated with an effective dose of 3 nmol/kg in a hyponatremic model, and then in polycystic kidney models on which MQ232 significantly reduced cyst growth. Conclusions: We demonstrated, employing diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD.

Comparative assessment of the nature of the combined action of insecticides: different methodical approaches

Introduction. Pesticide mixtures containing insecticide methomyl are commonly used in agriculture. However, the interaction of their active ingredients in a mixture has been insufficiently studied. The purpose of the study was to evaluate the nature of the combined action of a mixture of insecticides methomyl (carbamate) and bifenthrin (pyrethroid) using various methods: a classical model (orthogonal planning of the experiment using nonlinear variables); a generalized linear regression model for the binomial distribution (probit regression); and an isobologram. The study was conducted at the Federal Scientific Center of Hygiene named after F.F. Erisman of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing, according to the protocol approved by the local bioethical commission. Materials and methods. Ninety male outbred rats were administered 9 combined doses of the insecticides (combinations of LD16, LD33 and LD50 for the individual compounds, as devised from a preliminary study). Results. Impaired coordination, tremor of the limbs and head, turning into convulsions, rapid (shallow) breathing were observed in all groups. The data on mortality as used to construct 2 mathematical models, as well as to construct an isobologram. Limitations. The study was limited to studying the indicators of acute oral toxicity, without taking into account the possible repeated exposure. Conclusion. The models showed that the additive effect for the combination of methomyl and bifenthrin was only observed for combinations when the individual dose of bifenthrin was equal to or greater than 45 mg/kg b.w. (LD33) and the dose of methomyl was less than 30 mg/kg b.w., as all animals receiving a dose of 30 mg/kg b.w. of methomyl (LD50) in the mixture died. Therefore, the dose of methomyl dictated the toxic effect of the mixture, which should be accounted for in hygienic regulation of methomyl-containing formulations.

Exploring Saffron's Therapeutic Potential: Insights on Phytochemistry, Bioactivity, and Clinical Implications.

Saffron, derived from the Crocus sativus plant, has been revered for centuries for its culinary, medicinal, and cultural significance. This review provides a comprehensive overview of saffron's chemical constituents and phytochemistry, elucidating its rich profile of bioactive compounds. Emphasis is placed on exploring the bio-accessibility, bioavailability, and bioactivity of saffron's phytochemicals, laying the foundation for understanding its pharmaceutical significance. The pharmaceutical importance of saffron and its phytochemicals is thoroughly examined, focusing on their diverse therapeutic properties. These include anticancer, antidiabetic, antioxidant, antimicrobial, anti-inflammatory, antinociceptive, anticonvulsant, antidepressant, learning and memory enhancement, cardiovascular, and antihypertensive properties. Such multifaceted pharmacological activities underscore saffron's potential as a valuable medicinal resource. Clinical studies investigating the efficacy and safety of saffron in various health conditions are synthesized, providing insights into its clinical applications. Moreover, toxicity assessments in animal models, encompassing acute, subacute, subchronic, and developmental toxicity, are discussed to delineate the safety profile of saffron and its bioactive constituents. Finally, recent advances and future perspectives in saffron research are highlighted, underscoring emerging trends and potential avenues for further exploration. This review serves as a comprehensive resource for researchers, clinicians, and stakeholders interested in harnessing the therapeutic potential of saffron while ensuring its safe and effective utilization in healthcare settings.

Cyperus articulatus: Anti-inflammatory and antinociceptive activity of a medicinal plant from the Amazon

Ethnopharmacological relevanceCyperus articulatus L., popularly known as priprioca, is a plant used in the Amazon for perfumed baths and homemade perfumes. In traditional medicine, its rhizomes are used to treat diseases related to inflammatory processes. Aim of the studyDue to its promising bioactive properties, this study sought to investigate its phytochemistry and the anti-inflammatory and antinociceptive activity of the essential oil obtained from C. articulatus (CAEO) in in vitro and in vivo tests. Material and methodsThe essential oil was obtained from the rhizomes of C. articulatus and extraction was carried out via hydrodistillation. Then, the oil was analyzed by GC-MS analyses. Initially, culture of RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) was used to evaluate cytotoxicity and interference in the production of mediators of the inflammatory process (nitrite, IL-1β, TNF-α and PGE2) after exposure to CAEO. The acute toxicity of CAEO was evaluated and the results were used to define doses of 10, 100 and 400 mg kg−1 for evaluation of CAEO in in vivo tests using mice. The carrageenan-induced air pouch models and the Evans test were used to evaluate the anti-inflammatory activity by measuring the number of total leukocytes and vascular permeability. Antinociceptive activity was evaluated via tests of contortions induced by acetic acid, hot plate, and formalin. ResultsTreatment with CAEO reduced the levels of nitrite IL-1β, TNF-α and PGE2 in the macrophage culture, revealing its anti-inflammatory potential. CAEO decreased carrageenan-induced leukocyte migration and vascular permeability, which are important events related to the acute inflammatory response. Nociceptive activity was significantly inhibited by CAEO in the acetic acid-induced contortions model, hot plate, and in both phases of the formalin test. The treatment with naloxane reversed the antinociceptive effect observed in the formalin test, suggesting the participation of opioid receptors in the mechanism of action of CAEO. ConclusionThe observed results reveal the anti-inflammatory and antinocipeptive activity of C. articulatus essential oil in vivo and support the traditional use of this plant in the treatment of different diseases involving inflammation and pain.