Journal of Xenobiotics

In the age of industrialization, numerous non-biodegradable pollutants like plastics, HMs, polychlorinated biphenyls, and various agrochemicals are a serious concern. These harmful toxic compounds pose a serious threat to food security because they enter the food chain through agricultural land and water. Physical and chemical techniques are used to remove HMs from contaminated soil. Microbial-metal interaction, a novel but underutilized strategy, might be used to lessen the stress caused by metals on plants. For reclaiming areas with high levels of heavy metal contamination, bioremediation is effective and environmentally friendly. In this study, the mechanism of action of endophytic bacteria that promote plant growth and survival in polluted soils—known as heavy metal-tolerant plant growth-promoting (HMT-PGP) microorganisms—and their function in the control of plant metal stress are examined. Numerous bacterial species, such as Arthrobacter, Bacillus, Burkholderia, Pseudomonas, and Stenotrophomonas, as well as a few fungi, such as Mucor, Talaromyces, Trichoderma, and Archaea, such as Natrialba and Haloferax, have also been identified as potent bioresources for biological clean-up. In this study, we additionally emphasize the role of plant growth-promoting bacteria (PGPB) in supporting the economical and environmentally friendly bioremediation of heavy hazardous metals. This study also emphasizes future potential and constraints, integrated metabolomics approaches, and the use of nanoparticles in microbial bioremediation for HMs. Full article

With the legalization of marijuana smoking in several states of the United States and many other countries for medicinal and recreational use, the possibility of its release into the environment cannot be overruled. Currently, the environmental levels of marijuana metabolites are not monitored on a regular basis, and their stability in the environment is not well understood. Laboratory studies have linked delta 9-tetrahydrocannabinol (Δ⁹-THC) exposure with behavioral abnormalities in some fish species; however, their effects on endocrine organs are less understood. To understand the effects of THC on the brain and gonads, we exposed adult medaka (Oryzias latipes, Hd-rR strain, both male and female) to 50 ug/L THC for 21 days spanning their complete spermatogenic and oogenic cycles. We examined transcriptional responses of the brain and gonads (testis and ovary) to Δ⁹-THC, particularly molecular pathways associated with behavioral and reproductive functions. The Δ⁹-THC effects were more profound in males than females. The Δ⁹-THC-induced differential expression pattern of genes in the brain of the male fish suggested pathways to neurodegenerative diseases and pathways to reproductive impairment in the testis. The present results provide insights into endocrine disruption in aquatic organisms due to environmental cannabinoid compounds. Full article

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI. Full article

Accurate predictions of drug uptake transporter involvement in renal excretion of xenobiotics require determination of in vitro transport kinetic parameters under initial-rate conditions. The purpose of the present study was to determine how changing the incubation time from initial rate to steady state influences ligand interactions with the renal organic anion transporter 1 (OAT1), and the impact of the different experimental conditions on pharmacokinetic predictions. Transport studies were performed with Chinese hamster ovary cells expressing OAT1 (CHO-OAT1) and the Simcyp Simulator was used for physiological-based pharmacokinetic predictions. Maximal transport rate and intrinsic uptake clearance (CL_int) for PAH decreased with increasing incubation time. The CL_int values ranged 11-fold with incubation times spanning from 15 s (CL_int,15s, initial rate) to 45 min (CL_int,45min, steady state). The Michaelis constant (K_m) was also influenced by the incubation time with an apparent increase in the Km value at longer incubation times. Inhibition potency of five drugs against PAH transport was tested using incubation times of either 15 s or 10 min. There was no effect of time on inhibition potency for omeprazole or furosemide, whereas indomethacin was less potent, and probenecid (~2-fold) and telmisartan (~7-fold) more potent with the longer incubation time. Notably, the inhibitory effect of telmisartan was reversible, albeit slowly. A pharmacokinetic model was developed for PAH using the CL_int,15s value. The simulated plasma concentration-time profile, renal clearance, and cumulative urinary excretion-time profile of PAH agreed well with reported clinical data, and the PK parameters were sensitive to the time-associated CL_int value used in the model. Full article

According to recent literature, there is a limited amount of data about the correlation of vitamin 25(OH)D, potassium (K), oxidative stress parameters, and other biomarkers with dyslipidemia, which is an established risk factor for cardiovascular diseases (CVDs). This study aims to investigate the correlation of lipid profile and atheromatic index TC/HDL with several biomarkers and oxidative stress parameters. A total of 102 volunteers, 67 with atheromatic index TC/HDL > 3.5 (Group A) and 35 with TC/HDL < 3.5 (Group B), aged from 26 to 78 years, participated in this study. Serum levels of triglycerides (TG), total cholesterol (TC), low- and high-density lipoproteins (LDL and HDL), vitamin 25(OH)D [25(OH)D], potassium (K), sodium (Na), lactose dehydrogenase (LDH), liver enzymes including serum glutamic oxaloacetic and glutamic pyruvic transaminases (SGOT and SGPT), gamma-glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) were analyzed using standard photometric methods. Oxidative stress parameters such as reactive oxygen species (ROS) were detected with fluorometric methods, whereas total oxidative (TOS) and antioxidative status (TAS) were measured with spectrophotometric methods. According to the results, negative correlations of HDL (r = −0.593) and 25(OH)D (r = −0.340) and K (r = −0.220) were found, and positive expected correlations of LDL (r = 0.731), TC (r = 0.663), and TG (r = 0.584) with atheromatic index in the total studied sample were found. In conclusion, patients with a dyslipidemic profile should frequently check not only their lipid profile but also other biomarkers such as 25(OH)D, potassium, and oxidative stress markers to predict dyslipidemia and avoid subsequent disorders. Full article

The role of intestinal barrier homeostasis in an individual’s general well-being has been widely addressed by the scientific community. Colorectal cancer is among the illnesses that most affect this biological barrier. While chemotherapy is the first choice to treat this type of cancer, multidrug resistance (MDR) is the major setback against the commonly used drugs, with the ATP-binding cassette transporters (ABC transporters) being the major players. The role of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), or breast cancer resistance protein (ABCG2) in the efflux of chemotherapeutic drugs is well described in cancer cells, highlighting these proteins as interesting druggable targets to reverse MDR, decrease drug dosage, and consequently undesired toxicity. Natural products, especially phytochemicals, have a wide diversity of chemical structures, and some particular classes, such as phenolic acids, flavonoids, or pentacyclic triterpenoids, have been reported as inhibitors of P-gp, MRP1, and ABCG2, being able to sensitize cancer cells to chemotherapy drugs. Nevertheless, ABC transporters play a vital role in the cell’s defense against xenobiotics, and some phytochemicals have also been shown to induce the transporters’ activity. A balance must be obtained between xenobiotic efflux in non-tumor cells and bioaccumulation of chemotherapy drugs in cancer cells, in which ABC transporters are essential and natural products play a pivotal role that must be further analyzed. This review summarizes the knowledge concerning the nomenclature and function of ABC-transporters, emphasizing their role in the intestinal barrier cells. In addition, it also focuses on the role of natural products commonly found in food products, e.g., phytochemicals, as modulators of ABC-transporter activity and expression, which are promising nutraceutical molecules to formulate new drug combinations to overcome multidrug resistance. Full article

The current study emphasizes fungi as an important tool against heavy metals and how isolated fungal species can be used to create a successful strategy for the bioremediation of chromium and arsenic-contaminated sites/soils. Globally, heavy metal pollution is a serious issue. In the current investigation, contaminated sites were chosen, and samples could be taken from various localities of Hisar (29.1492° N, 75.7217° E) and Panipat (29.3909° N, 76.9635° E), India. A total of 19 fungal isolates were obtained from the collected samples through the enrichment culture technique using PDA media supplemented with Cr as chromic chloride hexahydrate (50 mg/L) and As as sodium arsenate (10 mg/L) and the potential of fungal isolates to be used for the removal of heavy metals was examined. The isolates were screened for minimum inhibitory concentrations (MIC) exhibiting tolerance capabilities, and the four best isolates C1, C3, A2, and A6 with the highest MICs (>5000 mg/L), were chosen for further investigations. To use the chosen isolates in the remediation of heavy metals (Cr and As), the culture conditions were optimized. The fungal isolates C1 and C3 estimated the highest removal of 58.60% and 57.00% at 50 mg/L chromium concentration, while the isolates A6 and A2 recorded the highest removal efficiency of 80% and 56% at 10 mg/L arsenic concentration under optimal conditions. Finally, the chosen fungal isolates C1 and A6 were molecularly identified as Aspergillus tamarii and Aspergillus ustus, respectively. Full article

Isometamidium chloride (ISM) is a trypanocide for the prophylactic and therapeutic use against vector-borne animal trypanosomosis (mainly Surra caused by Trypanosoma evansi) and African animal trypanosomosis caused by T. congolense/T. vivax/T. brucei). ISM was found to be an efficient trypanocide for therapeutic/prophylactic use against trypanosomosis; however, it produces some local and systemic detrimental effects in animals. We synthesized isometamidium chloride-loaded alginate gum acacia nanoformulation (ISM SANPS) to lessen the detrimental side effects of isometamidium chloride (ISM) while treating trypanosomal diseases. We intended to determine the cytocompatibility/toxicity, and DNA deterioration/chromosomal structural or number changes (genotoxicity) of ISM SANPs using mammalian cells in a concentration-dependent manner. Apurinic/apyrimidinic (AP) sites are one of the major types of DNA lesions formed during base excision and repair of oxidized, deaminated, or alkylated bases. The intensity of the cellular AP site is an excellent marker of the deterioration of DNA quality. We thought it pertinent to quantify the AP sites in ISM SANPs-treated cells. Our investigations established a dose-dependent cyto-compatibility or toxicity and DNA impairment (genotoxicity) in ISM SANPs-treated horse peripheral blood mononuclear cells. ISM SANPs were biocompatible at various concentrations tested on the mammalian cells. Full article

The effect of copper and nickel ions on the lipid composition of freshwater mussels Anodonta cygnea was investigated using an aquarium experiment. The contents of the main lipid classes were determined using thin layer chromatography and spectrophotometry, and the fatty acid composition was analysed using gas–liquid chromatography. The results indicated that copper and nickel had different effects on the mussels’ lipid composition, with copper producing less effect on the composition of lipids and fatty acids than nickel. On the first experiment day, excessive copper content in the organism caused oxidative stress and modifications in membrane lipids, which returned to their initial level by the end of the experiment. Nickel accumulated predominantly in gills; however, significant modifications in lipids and fatty acids were seen also in the digestive gland from the first day of the experiment. This indicated the activation of nickel-induced lipid peroxidation processes. Moreover, this study revealed a dose-dependent effect of nickel on lipid composition, which was likely related to the development of compensatory biochemical mechanisms in response to nickel-induced oxidative stress. A comparative study of the lipid composition alteration in mussels in response to copper and nickel action revealed the consequences of the toxic impact of metal ions and the defensive mechanisms that organisms employ to detoxify and remove xenobiotics. Full article

Fragrance compounds (synthetic fragrances or natural essential oils) comprise formulations of specific combinations of individual materials or mixtures. Natural or synthetic scents are core constituents of personal care and household products (PCHPs) that impart attractiveness to the olfactory perception and disguise the unpleasant odor of the formula components of PCHPs. Fragrance chemicals have beneficial properties that allow their use in aromatherapy. However, because fragrances and formula constituents of PCHPs are volatile organic compounds (VOCs), vulnerable populations are exposed daily to variable indoor concentrations of these chemicals. Fragrance molecules may trigger various acute and chronic pathological conditions because of repetitive human exposure to indoor environments at home and workplaces. The negative impact of fragrance chemicals on human health includes cutaneous, respiratory, and systemic effects (e.g., headaches, asthma attacks, breathing difficulties, cardiovascular and neurological problems) and distress in workplaces. Pathologies related to synthetic perfumes are associated with allergic reactions (e.g., cutaneous and pulmonary hypersensitivity) and potentially with the perturbation of the endocrine-immune-neural axis. The present review aims to critically call attention to odorant VOCs, particularly synthetic fragrances and associated formula components of PCHPs, potentially impacting indoor air quality and negatively affecting human health. Full article

Compounds from Zanthoxylum chalybeum Engl. were previously reported for inhibitory activities of amylase and glucosidase enzymatic action on starch as a preliminary study toward the establishment of a management strategy against postprandial hyperglycemia, however, the inhibitory kinetics and molecular interaction of these compounds were never established. A study was thus designed to establish the inhibitory kinetics and in silico molecular interaction of α-glucosidase and α-amylase with Z. chalybeum metabolites based on Lineweaver–Burk/Dixon plot analyses and using Molecular Operating Environment (MOE) software, respectively. Skimmianine (5), Norchelerythrine (6), 6-Acetonyldihydrochelerythrine (7), and 6-Hydroxy-N-methyldecarine (8) alkaloids showed mixed inhibition against both α-glucosidase and α-amylase with comparable K_i to the reference acarbose (p > 0.05) on amylase but significantly higher activity than acarbose on α-glucosidase. One phenolic 2,3-Epoxy-6,7-methylenedioxyconiferol (10) showed a competitive mode of inhibition both on amylase and glucosidase which were comparable (p > 0.05) to the activity of acarbose. The other compounds analyzed and displayed varied modes of inhibition between noncompetitive and uncompetitive with moderate inhibition constants included chaylbemide A (1), chalybeate B (2) and chalybemide C (3), fagaramide (4), ailanthoidol (9), and sesame (11). The important residues of the proteins α-glucosidase and α-amylase were found to have exceptional binding affinities and significant interactions through molecular docking studies. The binding affinities were observed in the range of −9.4 to −13.8 and −8.0 to −12.6 relative to the acarbose affinities at −17.6 and −20.5 kcal/mol on α-amylase and α-glucosidase residue, respectively. H-bonding, π-H, and ionic interactions were noted on variable amino acid residues on both enzymes. The study thus provides the basic information validating the application of extracts of Z. chalybeum in the management of postprandial hyperglycemia. Additionally, the molecular binding mechanism discovered in this study could be useful for optimizing and designing new molecular analogs as pharmacological agents against diabetes. Full article

In this work, a stability study of dispersions of graphene oxide and graphene oxide functionalized with polyethylene glycol (PEG) in the presence of bovine serum albumin is carried out. First, a structural characterization of these nanomaterials is performed by scanning electron microscopy, atomic force microscopy, and ultraviolet visible spectroscopy, comparing the starting nanomaterials with the nanomaterials in contact with the biological material, i.e., bovine fetal serum. The different experiments were performed at different concentrations of nanomaterial (0.125–0.5 mg/mL) and BSA (0.01–0.04 mg/mL), at different incubation times (5–360 min), with and without PEG, and at different temperatures (25–40 °C). The SEM results show that BSA is adsorbed on the surface of the graphene oxide nanomaterial. Using UV-Vis spectrophotometry, the characteristic absorption peaks of BSA are observed at 210 and 280 nm, corroborating that the protein has been adsorbed. When the time increases, the BSA protein can be detached from the nanomaterial due to a desorption process. The stability of the dispersions is reached at a pH between 7 and 9. The dispersions behave like a Newtonian fluid with viscosity values between 1.1 and 1.5 mPa·s at a temperature range of 25 to 40 °C. The viscosity values decrease as the temperature increases. Full article

Background: The use of herbs to treat illnesses was common in all historical eras. Our aim was to describe the phytotherapeutic substances that cancer patients use most commonly, and to determine whether their use can increase side effects. Methods: This was a retrospective and descriptive study conducted among older adults actively undergoing chemotherapy, admitted at the Oncology DH Unit (COES) of the Molinette Hospital AOU Città della Salute e della Scienza in Turin (Italy). Data collection was conducted through the distribution of self-compiled and closed-ended questionnaires during chemotherapy treatment. Results: A total of 281 patients were enrolled. Evaluating retching and sage consumption was statistically significant in multivariate analysis. The only risk factor for dysgeusia was chamomile consumption. Ginger, pomegranate, and vinegar use were retained as mucositis predictors. Conclusions: Phytotherapeutic use needs more attention in order to decrease the risks of side effects, toxicity, and ineffective treatment. The conscious administration of these substances should be promoted for safe use and to provide the reported benefits. Full article

Introduction. Since high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe. Methods. CA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Income was taken from the World Bank’s online sources. Results. On the bivariate maps of both orofacial clefts and holoprosencephaly against resin, the Δ9-tetrahydrocannabinol concentration rates of both covariates increased together in France, Bulgaria, and the Netherlands. In the bivariate analysis, the anomalies could be ranked by the minimum E-value (mEV) as congenital glaucoma > congenital cataract > choanal atresia > cleft lip ± cleft palate > holoprosencephaly > orofacial clefts > ear, face, and neck anomalies. When nations with increasing daily use were compared to those without, the former had generally higher rates of FCAs (p = 0.0281). In the inverse probability weighted panel regression, the sequence of anomalies—orofacial clefts, anotia, congenital cataract, and holoprosencephaly—had positive and significant cannabis coefficients of p = 2.65 × 10⁻⁵, 1.04 × 10⁻⁸, 5.88 × 10⁻¹⁶, and 3.21 × 10⁻¹³, respectively. In the geospatial regression, the same series of FCAs had positive and significant regression terms for cannabis of p = 8.86 × 10⁻⁹, 0.0011, 3.36 × 10⁻⁸, and 0.0015, respectively. Some 25/28 (89.3%) E-value estimates and 14/28 (50%) mEVs were >9 (considered to be in the high range), and 100% of both were >1.25 (understood to be in the causal range). Conclusion. Rising cannabis use is associated with all the FCAs and fulfils the epidemiological criteria for causality. The data indicate particular concerns relating to brain development and exponential genotoxic dose-responses, urging caution with regard to community cannabinoid penetration. Full article

Immune thrombocytopenic purpura (ITP) is an acquired antibody or cell-mediated platelet damage or decreased platelet production. Steroids, IV immunoglobulins (IVIG), and Rho-anti-D antibodies are the commonly used initial treatments for ITP. However, many ITP patients either do not respond or do not maintain a response to initial therapy. Splenectomy, rituximab, and thrombomimetics are the commonly used second-line treatment. More treatment options include tyrosine kinases inhibitors (TKI), including spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (BTK) inhibitors. This review aims to assess the safety and efficacy of TKIs. Methods: Literature was searched on PubMed, Embase, WOS, and clinicaltrials.gov using keywords, “tyrosine kinase” and “idiopathic thrombocytopenic purpura”. PRISMA guidelines were followed. Results: In total, 4 clinical trials were included with 255 adult patients with relapsed/refractory ITP. In all, 101 (39.6%) patients were treated with fostamatinib, 60 (23%) patients with rilzabrutinib, and 34 (13%) with HMPL-523. Patients treated with fostamatinib achieved a stable response (SR) and overall response (OR) in 18/101 (17.8%) and 43/101 (42.5%) of the patients, respectively, while SR and OR were achieved in 1/49 (2%) and 7/49 (14%) of the patients, respectively, in the placebo group. Patients treated with HMPL-523 (300 mg dose expansion) achieved an SR and OR in 5/20 (25%) and 11/20 (55%) of the patients, respectively, while SR and OR were achieved in 1/11 (9%) of the patients treated with the placebo. Patients treated with rilzabrutinib achieved an SR in 17/60 (28%) patients. Dizziness (1%), hypertension (2%), diarrhea (1%), and neutropenia (1%) were serious adverse events in fostamatinib patients. Rilzabrutinib or HMPL-523 patients did not require a dose reduction due to drug-related adverse effects. Conclusions: Rilzabrutinib, fostamatinib, and HMPL-523 were safe and effective in the treatment of relapsed/refractory ITP. Full article

The fight against malaria is a continuum as the epidemic is not abating. For proper deployment of tools in the fight against malaria, an assessment of the situation is necessary. This work assessed the level of antimalarial drug treatment failure in Ebonyi State, Nigeria. Both survey and in vitro analyses were adopted. The survey was used to obtain qualitative information from both the malaria subjects and the pharmacies where antimalarial drugs are sourced. The results from the survey were complemented by an in vitro assay of the level of active pharmaceutical ingredients (APIs) in the commonly used artemisinin combination in Nigeria; artemether/lumefantrine. Results from the survey revealed that artemisinin combination therapies (ACTs) remain the mainstay in the treatment of malaria, even though other non-artemisinin drugs are still used. It also revealed that many patients still self-medicate, although, this may not be connected to the treatment failure seen among some malaria subjects. The in vitro assay showed that ACT contains the right quantity of APIs. Further surveillance is, therefore, necessary to understand the real cause of treatment failure among malaria subjects in Nigeria. Full article

An analytical method for the quantitative determination of the insecticide spinetoram in cotton and soybean was established and validated using liquid chromatography tandem mass spectrometry (LC-MS/MS). Spinetoram is the mixture of two spinosyns, 3′-O-ethyl-5,6-dihydro spinosyn J and 3′-O-ethyl spinosyn L. The method involves extraction with ethyl acetate followed by dispersive solid phase extraction (dSPE) clean-up with primary secondary amine (PSA), C₁₈ and graphitised carbon black (GCB). The final quantitation of spinetoram was done by using LC-MS/MS with positive electrospray ionization. The method was reproducible (Horwitz ratio (HorRat) < 0.5 at 25 ng g⁻¹) and validated by the analysis of samples spiked at 25, 50 and 100 ng g⁻¹ in soybean, cotton and soil. The recoveries of spinosyns were found to be more than 85% when spiked at different levels. The identities of spinosyns were confirmed by using the ion ratio. A field dissipation study was conducted in soybean and cotton to find out the environmental fate of spinetoram, and samples were analysed following the proposed analytical method. Both isomers were found to be dissipated quickly. The pre-harvest interval of spinetoram was calculated in different substrates. Full article