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Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based "2 × 2" symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10–9 M for human PD1 and 2.557 × 10–8 M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009's anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50 h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150 mg/kg, while the repeated-dose (once weekly for 4 weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15 mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009's candidacy for its clinical development. [ABSTRACT FROM AUTHOR]

Bioherbicides are expected to be a supplement to integrated pest management, assisting in the control of problematic weed species. For instance, bioherbicides (Phoma and BioPhoma) were recently registered in Canada and the USA for the control of some perennial dicotyledonous weeds in lawns. These products are based on strains of the fungus Didymella macrostoma (syn. Phoma macrostoma) that causes white tip disease (WTD) in Canada thistle (Cirsium arvense). In this study, WTD was reported for the first time in the Russian Federation. Analysis of the internal transcribed spacer (ITS) region of nuc rDNA and secondary metabolite profiling confirmed the identity of Russian WTD isolates to Canadian biocontrol strains identified as D. macrostoma. Multilocus phylogenetic analysis based on sequencing of the ITS region, partial large subunit nuc rDNA region (28S), RNA polymerase II second largest subunit gene (rpb2), and partial β-tubulin gene (tub2) has differentiated the WTD isolates from C. arvense and D. macrostoma isolates from other plant hosts. Based on phylogenetic, morphological, and chemotaxonomic features, these WTD isolates were described as a new species named Didymella baileyae, sp. nov. This study also demonstrated the low pathogenicity of the ex-type D. baileyae isolate VIZR 1.53 to C. arvense seedlings and its asymptomatic development in the leaves of aboveground shoots. The organic extracts from mycelium and culture filtrate of D. baileyae, as well as macrocidin A and macrocidin Z, displayed phytotoxicity both to C. arvense leaves and seedlings. Macrocidin A was only detected in the naturally infected leaf tissues of C. arvense showing WTD symptoms. Macrocidins A and Z demonstrated low antimicrobial and cytotoxic activities, exhibiting no entomotoxic properties. The data obtained within this study on the pathogenicity and metabolites of D. baileyae may be important for the rational evaluation of its prospects as a biocontrol agent. [ABSTRACT FROM AUTHOR]

Background Conioselinum anthriscoides (H. Boissieu) Pimenov & Kljuykov, also known as Ligusticum chuanxiong Hort. is a perennial Umbelliferae herb, whose dried rhizome commonly called Chuanxiong Rhizoma. Chuanxiong Rhizoma is widely used in TCM, especially for cardiocerebrovascular and gynecological diseases. However, these studies are scattered and there is no review that can centralize the results of these studies. The authors summarized this review by collecting research results on the chemical, pharmacological, and toxicological of Chuanxiong Rhizoma published in various publications over the past 20 years. Aims The purpose of this review is to summarize the current experimental studies on Chuanxiong Rhizoma and explore its mechanism of action. Methods Web of Science, PubMed, CBM, CNKI, Medline, Embase, Elsevier, Springer, Wiley Online Library, Scholar, and other databases were searched, and nearly one hundred experimental studies were collected to summarize this review. Results and Discussion Chuanxiong Rhizoma is composed of essential oil, terpenes, alkaloids, polysaccharide, organic acids, ceramides, and cerebrosides. It has the functions of promoting blood circulation, removing blood stasis, antibacterial, antiviral, and calming the mind to sleep. Now it can be used to treat cardiocerebrovascular and gynecological diseases, neurodegenerative disease, psoriasis, rectal cancer, osteoporosis, and osteoarthritis. Conclusions In the past 20 years, a large number of research data have confirmed that Chuanxiong Rhizoma contains rich effective metabolites, has huge medicinal potential, and has a wide range of effective treatments. [ABSTRACT FROM AUTHOR]

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact. [ABSTRACT FROM AUTHOR]

Foraging provides a multitude of individual, social, and environmental benefits. With green spaces decreasing in the United Kingdom, there is an opportunity for roadside verges to become valuable foraging resources; however, there is public concern over the safety of roadside forage. Human ingestion of heavy metal contaminants, such as copper (Cu), lead (Pb), and cadmium (Cd), originating from traffic activity, induces toxic effects in the body. Therefore, maximum Cu, Pb, and Cd guideline limits for human consumption in small fruits were established. However, studies of heavy metal concentrations in roadside forage and the effects of surface washing on concentrations are limited. This study examined Cu, Pb, and Cd in washed and unwashed wild blackberries (Rubus fruticose L.) along a main road in Kent, UK, and compares the values with maximum guideline limits. In all 44 samples, Cu, Pb and Cd concentrations were well below the maximum guideline limit or daily reference intake (RI) value. Cu and Pb concentrations were below the maximum daily intake in every sample if foragers eat one portion (80 g) of berries a day, but consuming a larger quantity of berries per day (e.g., 1 kg) could lead to an intake above the guideline limit for Cu (1 mg) and Pb (0.1 mg), but not Cd (0.03 mg). Washing did not significantly reduce the concentrations of Cu (p = 0.174) or Cd (p = 0.752) in blackberries, but did significantly reduce the Pb concentration (p < 0.001). However, Pb concentration was below maximum guideline limits for every sample regardless of washing treatment. Thus, wild blackberries collected from the roadside were suitable for human consumption, although the findings are not representative of all foraged berries or road networks. Integr Environ Assess Manag 2024;20:2107–2115. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: Urban foraging is an ever‐popular activity that reaps individual, social, and environmental benefits, with blackberries (Rubus fruticose L.) being a near‐universally foraged product.Human ingestion of heavy metal contaminants such as copper (Cu), lead (Pb), and cadmium (Cd) originating from traffic activity can induce toxic effects in the body; therefore, maximum guideline limits for human consumption of small fruits have been established.Washing blackberries did not significantly reduce Cu or Cd concentrations but did reduce lead concentrations; however, Pb below maximum guideline limits even before washing. An 80g portion of blackberries was considered suitable for human consumption, but a larger (e.g., 1 kg) portion would be unsafe.These findings are not representative of all foraged material or roads, so future research should consider: (1) road type, condition, and traffic volume, (2) proximity of sample sites to roads, (3) other local sources of contamination, and (4) other metal/metalloid road traffic pollutants. [ABSTRACT FROM AUTHOR]

Cooking oil fumes (COFs) are widely acknowledged as substantial contributors to indoor air pollution, having detrimental effects on human health. Despite the existence of commercialized in vitro aerosol exposure platforms, assessment risks of aerosol pollutants are primarily evaluated based on multiwell plate experiments by trapping and redissolving aerosols to conduct comprehensive in vitro immersion exposure manner. Therefore, an innovative real-time exposure system for COF aerosol was constructed, featuring a self-designed microfluidic chip as its focal component. The chip was used to assess toxicological effects of in vitro exposure to COF aerosol on cells cultured at the gas–liquid interface. Meanwhile, we used transcriptomics to analyze genes that exhibited differential expression in cells induced by COF aerosol. The findings indicated that the MAPK signaling pathway, known for its involvement in inflammatory response and oxidative stress, played a crucial role in the biological effects induced by COF aerosol. Biomarkers associated with inflammatory response and oxidative stress exhibited corresponding alterations. Furthermore, the concentration of COF aerosol exposure and post-exposure duration exert decisive effects on these biomarkers. Thus, the study suggests that COF can induce oxidative stress and inflammatory response in BEAS-2B cells, potentially exerting a discernible impact on human health. [ABSTRACT FROM AUTHOR]

The (diphtheria, tetanus, and pertussis [acellular, component] [DTacP]) vaccine is a combined vaccine designed to prevent three potentially fatal diseases including pertussis, tetanus, and diphtheria in both children and adults. We utilized advanced technology to develop a novel DTacP vaccine that was previously unavailable in China. The nonclinical studies were performed to evaluate the immunogenicity, potential toxicity, and local tolerance of the vaccine in animal models. In the immunogenicity study, three batches of the vaccine were intraperitoneally administered to National Institutes of Health (NIH) mice, resulting in 100% seropositivity for all three batches. Additionally, antibody levels notably increased as the immunization dosage increased. In acute toxicity study, no mortality was observed among the animals during the 14‐day observation period, and no abnormalities in clinical signs were reported. Active systemic anaphylaxis assessment in guinea pigs showed no evidence of serious allergic reactions in the vaccine groups. In the repeat‐dose toxicity study, where five intramuscular doses were administered every 2 weeks, gross autopsy and histopathological examination revealed no vaccine‐related systemic pathological changes in rats, with dose site irritant reactions mostly recovered at the end of recovery period. In conclusion, the vaccine demonstrated good local and systemic tolerance, supporting its clinical development. We developed a novel DTacP vaccine that was previously unavailable in China and evaluated the immunogenicity, potential toxicity, and local tolerance of the vaccine in animal models. The seropositivity of vaccines reached 100% in mice. Acute toxicity study, active systemic anaphylaxis study, and repeat‐dose toxicity study showed no clinical signs abnormalities, and moderate irritant reactions were observed and mostly recovered at the end of recovery period. The DTacP vaccine demonstrated good local and systemic tolerance, supporting its clinical development. [ABSTRACT FROM AUTHOR]

Biogenic metallic nanoparticles (NPs) have garnered significant attention in recent years due to their unique properties and various applications in different fields. NPs, including gold, silver, zinc oxide, copper, titanium, and magnesium oxide NPs, have attracted considerable interest. Green synthesis approaches, utilizing natural products, offer advantages such as sustainability and environmental friendliness. The theranostics applications of these NPs hold immense significance in the fields of medicine and diagnostics. The review explores intricate cellular uptake pathways, internalization dynamics, reactive oxygen species generation, and ensuing inflammatory responses, shedding light on the intricate mechanisms governing their behaviour at a molecular level. Intriguingly, biogenic metallic NPs exhibit a wide array of applications in medicine, including but not limited to anti-inflammatory, anticancer, anti-diabetic, anti-plasmodial, antiviral properties and radical scavenging efficacy. Their potential in personalized medicine stands out, with a focus on tailoring treatments to individual patients based on these NPs' unique attributes and targeted delivery capabilities. The article culminates in emphasizing the role of biogenic metallic NPs in shaping the landscape of personalized medicine. Harnessing their unique properties for tailored therapeutics, diagnostics and targeted interventions, these NPs pave the way for a paradigm shift in healthcare, promising enhanced efficacy and reduced adverse effects. [ABSTRACT FROM AUTHOR]

The issue of microplastics (MPs) which are pervasive and ubiquitous pollutants, has given rise to a pressing need for a thorough understanding of them and the development of effective strategies to mitigate their impact. These tiny particles are derived from a wide array of human activities, including industrial processes, urban centers, and even our daily routines. To devise effective mitigation measures, it is essential to comprehend the sources and the complexity of their distribution across terrestrial, aquatic, and atmospheric domains, which adversely affect ecosystems worldwide. Extraction methods have been cultivated and established to remove MPs from the environment with higher efficiency. This paper elucidates the complexity of their dispersal and sheds light on the extraction methods along with their degradational strategies. It also discusses the use of machine learning models in MP identification, detection, and classification. The integration of machine learning, particularly with features extracted from holographic images and spectroscopic data offers a precise and efficient method for identifying MPs. The toxicological effects of MPs on organisms and ecosystems are also discussed, emphasizing the need for further research to mitigate their impact. The exploration of degradation strategies offers a promising solution to combat the pervasive presence of MPs. While several mechanisms contribute to MP degradation, microbial-driven processes have emerged as a dominant factor. This review delves deep into the realm of microbial degradation, highlighting its potential to transform the fate of these pollutants. The paper showcases the latest research and innovations, paving the way for an environmentally sustainable future. This comprehensive review emphasizes the urgency of addressing the MP predicament and presents a refined roadmap towards a sustainable future. [ABSTRACT FROM AUTHOR]

Humans can be exposed to per- and polyfluoroalkyl substances (PFASs) via many exposure routes, including diet, which may lead to several adverse health effects. So far, little is known about PFAS transport across the human intestinal barrier. In the current study, we aimed to assess the transport of 5 PFASs (PFOS, PFOA, PFNA, PFHxS and HFPO-DA) in a human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cell (IEC) model. This model was extensively characterized and compared with the widely applied human colonic adenocarcinoma cell line Caco-2 and a human primary IEC-based model, described to most closely resemble in vivo tissue. The hiPSC-derived IEC layers demonstrated polarized monolayers with tight junctions and a mucus layer. The monolayers consisted of enterocytes, stem cells, goblet cells, enteroendocrine cells, and Paneth cells that are also present in native tissue. Transcriptomics analysis revealed distinct differences in gene expression profiles, where the hiPSC-derived IECs showed the highest expression of intestinal tissue-specific genes relative to the primary IEC-based model and the Caco-2 cells clustered closer to the primary IEC-based model than the hiPSC-derived IECs. The order of PFAS transport was largely similar between the models and the apparent permeability (Papp) values of PFAS in apical to basolateral direction in the hiPSC-derived IEC model were in the following order: PFHxS > PFOA > HFPO-DA > PFNA > PFOS. In conclusion, the hiPSC-derived IEC model highly resembles human intestinal physiology and is therefore a promising novel in vitro model to study transport of chemicals across the intestinal barrier for risk assessment of chemicals. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology Background: Trastuzumab (Herceptin) is a recombinant DNA-derived humanized monoclonal antibody that the US Food and Drug Administration (FDA) approved in 1998 for metastatic human epidermal growth factor receptor 2 (HER2)- positive breast cancer therapy. It selectively binds to the extracellular domain of HER2 and mediates an antibody-dependent cellular toxicity in various tissues. Trastuzumab use alone does not typically cause aggressive ocular complications. However, herein is a case report of a patient presenting with corneal ulceration in both eyes and perforation in the left eye after 2 months of trastuzumab therapy. Case Report: A 59-year-old woman with a history of metastatic breast cancer receiving chemotherapy was consulted for ophthalmic evaluation. She denied any history of ocular conditions and complained of eyelid crusting and sandy sensation in both eyes for 2 weeks. She had been using antibiotic eyedrops for presumed eye infection before her vision deteriorated 3-4 days prior to presentation. A thorough workup for autoimmune and infectious diseases was unyielding. Ophthalmologic examination revealed multiple epithelial defects with ulceration in the right eye and a corneal ulcer with perforation in the left eye. Corneal cultures were negative. Orbital imaging revealed metastases with optic nerve compression. In conjunction with the oncology team, further trastuzumab treatment was deferred. Therapeutic keratoplasty along with ocular surface therapy eventually stabilized both eyes. Conclusions: Ocular adverse effects such as corneal epithelial changes and melts have been reported with trastuzumab. We recommend ophthalmology consultation for any ocular symptoms in patients on trastuzumab treatment. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is the second most diagnosed cancer, as well as the primary cause of cancer death in women worldwide. Of the different breast cancer subtypes, triple-negative breast cancer (TNBC) is particularly aggressive and is associated with poor prognosis. Black women are two to three times more likely to be diagnosed with TNBCs than white women. Recent experimental evidence suggests that basal-like TNBCs may derive from luminal cells which acquire basal characteristics through phenotypic plasticity, a newly recognized hallmark of cancer. Whether chemical exposures can promote phenotypic plasticity in breast cells is poorly understood. Methods: To investigate further, we developed a high-content immunocytochemistry assay using normal human breast cells to test whether chemical exposures can impact luminal/basal plasticity by unbiased quantification of keratin 14 (KRT14), a basal-myoepithelial marker; keratin 8 (KRT8), a luminal-epithelial marker; and Hoechst 33342, a DNA marker. Six cell lines established from healthy tissue from donors to the Susan G. Komen Normal Tissue Bank were exposed for 48 hours to three different concentrations (0.1μM, 1μM, and 10μM) of eight ubiquitous chemicals (arsenic, BPA, BPS, cadmium, copper, DDE, lead, and PFNA), with documented exposure disparities in US Black women, in triplicate. Automated fluorescence image quantification was performed using Cell Profiler software, and a random-forest classifier was trained to classify individual cells as KRT8 positive, KRT14 positive, or hybrid (both KRT8 and KRT14 positive) using Cell Profiler Analyst. Results and discussion: Results demonstrated significant concentrationdependent increases in hybrid populations in response to BPA, BPS, DDE, and PFNA. The increase in hybrid populations expressing both KRT14 and KRT8 is indicative of a phenotypically plastic progenitor-like population in line with known theories of carcinogenesis. Furthermore, BPA, BPS, DDE, and copper produced significant increases in cell proliferation, which could be indicative of a more malignant phenotype. These results further elucidate the relationship between chemical exposure and breast phenotypic plasticity and highlight potential environmental factors that may impact TNBC risk. [ABSTRACT FROM AUTHOR]

Environmental risk assessment (ERA) is critical for protecting life by predicting population responses to contaminants. However, routine toxicity testing often examines only one genotype from surrogate species, potentially leading to inaccurate risk assessments, as natural populations typically consist of genetically diverse individuals. To evaluate the importance of intraspecific variation in translating toxicity testing to natural populations, we quantified the magnitude of phenotypic variation between 20 Daphnia magna clones exposed to two levels of microcystins, a cosmopolitan cyanobacterial toxin. We observed significant genetic variation in survival, growth, and reproduction, which increased under microcystins exposure. Simulations of survival showed that using a single genotype for toxicity tolerance estimates on average failed to produce accurate predictions within the 95% confidence interval over half of the time. Whole genome sequencing of the 20 clones tested for correlations between toxicological responses and genomic divergence, including candidate loci from prior gene expression studies. We found no overall correlations, indicating that clonal variation, rather than variation at candidate genes, predicts population-level responses to toxins. These results highlight the importance of incorporating broad intraspecific genetic variation, without focusing specifically on variation in candidate genes, into ERAs to more reliably predict how local populations will respond to contaminants. [ABSTRACT FROM AUTHOR]

Marine mammals are integral to global biodiversity and marine health through their roles in coastal, benthic, and pelagic ecosystems. Marine mammals face escalating threats from climate change, pollution, and human activities, which perturb their oceanic environment. The diverse biology and extreme adaptations evolved by marine mammals make them important study subjects for understanding anthropogenic pressures on marine ecosystems. However, ethical and logistical constraints restrict the tractability of experimental research with live marine mammals. Additionally, studies on the effects of changing ocean environments are further complicated by intricate geneenvironment interactions across populations and species. These obstacles can be overcome with a comprehensive strategy that involves a systems-level approach integrating genotype to phenotype using rigorously defined experimental conditions in vitro and ex vivo. A thorough analysis of the interactions between the genetics of marine mammals and their exposure to anthropogenic pressures will enable robust predictions about how global environmental changes will affect their health and populations. In this perspective, we discuss four challenges of implementing such non-invasive approaches across scientific fields and international borders: 1) practical and ethical limitations of in vivo experimentation with marine mammals, 2) accessibility to relevant tissue samples and cell cultures; 3) open access to harmonized methods and datasets and 4) ethical and equitable research practices. Successful implementation of the proposed approach has the potential impact to inspire new solutions and strategies for marine conservation. [ABSTRACT FROM AUTHOR]

Natural compounds and their derivatives have been identified as valuable sources of therapeutic ingredients for cancer treatment. The naturally occurring phytochemical palmatine (isoquinoline alkaloid) is extracted from plant parts (rhizomes, roots, stems, stem barks, and others) and has protective effects including antioxidant, anti‐inflammatory, and anticancer. This study aims to summarize the anticancer potential of palmatine and its derivatives in the treatment of numerous types of cancer with molecular mechanisms. We also include the pharmacokinetic features, botanical origin, and toxicological characteristics of palmatine and its derivatives. For this, data have been collected from plausible different electronic databases, including PubMed, Google Scholar, PubChem, Science Direct, Web of Science, Scopus, Springer Link, and Wiley Online. The findings demonstrate that palmatine and its derivatives have a protective anticancer effect against a variety of cancers, including breast, colorectal, gastric, ovarian, prostate, pancreatic, skin, hepatocellular cancer, and mammary gland tumors. They provoke their anticancer properties against various cancer cell lines via modifying molecular mechanisms like induction of oxidative stress, cytotoxicity, apoptosis, inhibition of cell invasion and migration, arresting the cell cycle at the S phase, antiproliferative, and antiangiogenic effects. It is suggested that palmatine and its derivatives may be a good option in the development of novel drugs for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Summary: The present study aimed to introduce Avicenna's views on pest control and the medicinal plants he proposed as natural pesticides. Also, we addressed the strategies that he leveraged to formulate and prescribe them, and, finally, we put his views into perspective with modern science. The data were collected using Al-Qanun Fi Al-Tibb (The Canon of Medicine) as well as scientific databases. According to Al-Qanun Fi Al-Tibb, 42 medicinal plants are described as natural pest control agents. After introducing the pest control properties of each plant, Avicenna explained the appropriate strategies for use of these plants. These strategies or formulations included incensing, spraying, spreading, rubbing, smudging, and scent-dispersing, which are equivalent to the modern pesticide formulations of fumigants, aerosols, pastes and poisoned baits, lotions, creams, and slow-release formulations, respectively. This study revealed that Avicenna introduced the pest control approach with natural plants in his book Al-Qanun Fi Al-Tibb and, thus, harnessed the power of nature to control nature. Future research is recommended to find the pest control merits of the presented medicinal plants, in order to incorporate them into pest control programs and reduce environmental pollution resulting from the complications of current synthetic pesticides. [ABSTRACT FROM AUTHOR]

Summary: The current research aimed to analyze the history of bioterrorism in antiquity and to adapt the data to modern medical knowledge. To this end, a thorough evaluation of the literature related to the ancient history of bioterrorism and modern data was done using the Web of Sciences, Science Direct, Scopus, PubMed, and Google Scholar. Results showed that knowledge of bioterrorism has existed since antiquity in different civilizations. Biological and toxicological agents were used as an instrument of legal execution, as a warfare tool in battles, or to eliminate political rivals across nations. Ancient people researched bioterrorism to apply it against enemies and at the same time provide countermeasures in favor of themselves and allies. Despite the existence of the principles of bioterrorism since ancient times, adaptation of the data to modern research can assist in planning countermeasure efforts, preventive actions, and treatments in the framework of modern counterterrorism medicine. [ABSTRACT FROM AUTHOR]

Juglanin (kaempferol 3-O-α-L-arabinofuranoside) is a flavonol glycoside occurring in many plants, including its commercial sources Juglans regia, Polygonum aviculare and Selliguea hastata. Recent extensive studies have explored the potential of using juglanin in various pathological conditions, including cardiovascular disorders, central nervous and skeletal system disorders, metabolic syndrome, hepatic injury, and cancers. The results indicated a wide range of effects, like anti-inflammatory, anti-oxidant, anti-fibrotic, anti-thrombotic, anti-angiogenic, hepatoprotective, hypolipidemic, hypoglycemic, anti-apoptotic (normal cells), and pro-apoptotic (cancer cells). The health-promoting properties of juglanin can be attributed to its influence on many signaling pathways, associated with SIRT1, AMPK, Nrf2, STING, TLR4, MAPKs, NF-κB, AKT, JAK, and their downstream genes. This review primarily summarizes the current knowledge of molecular mechanisms, pharmacokinetics, biocompatibility, and human use safety of juglanin. In addition, the most promising new plant sources and other existing challenges and prospects have also been reviewed and discussed, aiming to provide direction and rationale for the further development and broader pharmaceutical application of juglanin. [ABSTRACT FROM AUTHOR]

Objective: This study examines the results of toxicological tests performed on blood and urine samples collected from suspected drug-impaired drivers in Ontario from 2008 to 2019. The report examines the results of toxicological analysis of the samples submitted, the characteristics of those drivers from whom samples were collected, and the temporal and situational circumstances that led to police investigations and sample collection to better understand drug-impaired driving behavior and to assist in the development and implementation of countermeasure strategies and programs. Methods: Blood and urine samples were sent to the Center of Forensic Sciences where they were analyzed using standardized comprehensive toxicological analysis to test for a wide variety of potentially impairing drugs. Demographic and temporal information for each case from which a sample was collected were also examined to describe the circumstances and characteristics of these driving incidents. Results: During the 12-year period examined, 5,388 samples collected from suspected drug-impaired drivers were analyzed. The number of samples collected increased substantially following the implementation of the Drug Evaluation and Classification Program (DECP) in July 2008, the enactment of legislation facilitating the collection of blood samples from suspects, and the legalization of cannabis for nonmedical purposes in 2018. The number of samples submitted shows temporal correlation with the number of police officers certified as Drug Recognition Experts (DRE) in the province. Over the 12-year period of this study, cannabis was the most frequently detected substance in drivers (52.8% of cases), followed by cocaine (44.3%) and methamphetamine (24.8%). In 80% of cases, more than one substance was detected. Conclusions: Examining the characteristics of suspected drug-impaired drivers, the temporal circumstances, and the drug findings throughout the large geographic area of Ontario and over the extended period of this study enhances our understanding of drug-impaired driving behavior. These characteristics can assist in the development and/or evaluation of enforcement strategies and enhanced countermeasure activities. [ABSTRACT FROM AUTHOR]

This review provides evidence on the genetic diversity, chemical constituents, and ecotoxicology of Mesosphaerum suaveolens' essential oil. It emphasizes the agricultural benefits such as crop protection effectiveness of the plant and highlights the existing knowledge gaps and research perspectives to promote its utilization in agriculture. A systematic and extensive review of the literature was done and all pertinent full-text articles and abstracts were analyzed and incorporated into the review. Mesosphaerum suaveolens is used traditionally in pharmacology to treat several diseases such as malaria, constipation, stomach problems, and renal inflammation. It also treats cramps, digestive infections, headaches, and skin infections. To date, very few studies have been conducted worldwide about its genetic diversity. These studies highlighted three morphological variants, the blue-flowering, the white-flowering, and the lightpurple flowering M. suaveolens. Its wide biological actions may be attributed to the numerous groups of chemical constituents in its essential oil including monoterpenes, sesquiterpenes, and diterpenes. Biological studies highlighted evidence of M. suaveolens being used as an antifungal, bactericidal, antimicrobial, insecticidal, and repellent plant. The essential oil extracted from M. suaveolens showed significant potential for the control of agricultural pests such as Sitiophilus zeamais, Helicoverpa armigera and Helminthosporium oryzae. M. suaveolens is commonly used worldwide as a pesticidal plant in healthcare, agriculture, and food preservation. However, there is a lack of studies concerning the toxicity and effectiveness of isolated potent phytotoxic substances, the efficacy screening in the field, the genetic diversity, the essential oil yield, and productivity. Consequently, further studies are required to fill the knowledge gaps. [ABSTRACT FROM AUTHOR]

This article aims to provide a comprehensive critical, yet readable, review of general interest to the chemistry community on molecular similarity as applied to chemical informatics and predictive modeling with a special focus on read-across (RA) and read-across structure–activity relationships (RASAR). Molecular similarity-based computational tools, such as quantitative structure–activity relationships (QSARs) and RA, are routinely used to fill the data gaps for a wide range of properties including toxicity endpoints for regulatory purposes. This review will explore the background of RA starting from how structural information has been used through to how other similarity contexts such as physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties, and biological aspects are being characterized. More recent developments of RA's integration with QSAR have resulted in the emergence of novel models such as ToxRead, generalized read-across (GenRA), and quantitative RASAR (q-RASAR). Conventional QSAR techniques have been excluded from this review except where necessary for context. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the toxicological action of AH Plus (AHP), Bio-C Sealer (BCS), and EndoSequence BC Sealer (ESB), using Drosophila melanogaster as the model organism performing in vivo and ex vivo analysis. D. melanogaster were exposed for 10 days to three concentrations (5 mg/ml, 10 mg/ml, and 20 mg/ml) of AHP, BCS, and ESB sealers mixed with 10 ml of standard diet. During this period, the mortality of flies was evaluated. On the 11th day, the locomotor activity test was performed and the flies were euthanized for oxidative damage analysis (reactive species and lipid peroxidation) and cell viability (resazurin reduction). For the mortality curves evaluation, the log-rank test (Mantel–Cox) was used. For the analysis of other data, a one-way analysis of variance (ANOVA) was applied, followed by Tukey's post hoc test (α = 0.05). Regarding mortality, there were no significant differences. The locomotor activity was reduced, mainly in the two highest concentrations of AHP and BCS. Besides, reactive species generation was bigger in the AHP 20 mg/ml group. AHP induced a lipid peroxidation increase in all three concentrations tested, when compared to other sealers. Considering cell viability, the two highest concentrations of AHP reduced this parameter; while in other sealers, viability was reduced only in the highest concentration. AHP showed changes in oxidative markers that led to greater damage to the flies. [ABSTRACT FROM AUTHOR]

This comprehensive review provides a thorough exploration of a mounting environmental issue: heavy metal contamination in aquatic ecosystems and its far-reaching impacts on fish populations and human health. Starting with the generalized sources of different heavy metals that lead to their entry into the aquatic environment, this review then considers each of the major heavy metals (copper, cadmium, chromium, arsenic, nickel, lead, zinc, and mercury) and ventures deep into the intricate mechanisms governing the uptake, bioaccumulation, and toxicity of heavy metals in fish, shedding light on the profound consequences these processes have for fish health and behavior. A critical aspect emphasized in this article is the activation of antioxidant defense mechanisms and involvement of metallothionein in fish as an adaptive response aimed at mitigating the pervasive oxidative stress triggered by heavy metal exposure. Of utmost concern is the trophic transfer of heavy metals from contaminated fish to humans through consumption, which poses a direct threat to human health regarding various physiological functions. The article underscores the urgency of addressing this issue comprehensively. Given the concerning discoveries at hand, this review fervently supports the enactment of rigorous regulations, the embracing of sustainable management techniques, and the stringent enforcement of pollution containment strategies. [ABSTRACT FROM AUTHOR]

This study assessed the presence of eight pesticide residues in the Indus River, Mianwali, Pakistan, focusing on three sampling sites (S1, S2, and S3) in water, sediment, and the fish species Cyprinus carpio during both dry and wet seasons. Analysis was conducted using gas chromatography with an electron capture detector. Results indicated elevated pesticide concentrations in both seasons, with levels of 0.84 and 0.62 μg/L in water, 12.47 and 9.21 μg/g/dw in sediment, and 17.33 and 12.17 μg/g/ww in fish, with higher concentrations observed during the dry season. Cypermethrin and carbofuran were the primary pesticides detected in water, while endosulfan and cypermethrin were dominant in sediment and fish tissue, often exceeding standard safety thresholds. Principal Component Analysis (PCA) and cluster analysis revealed stronger correlations between sediment and fish muscle, with varying associations among pesticides across seasons. The Hazard Index (HI) surpassed 1 in both seasons, signaling potential health risks to humans. These findings underscore the substantial risk agricultural pesticides pose to the aquatic ecosystem and food chain, highlighting the urgent need for sustainable agricultural practices and stricter regulations to minimize pesticide use and encourage eco-friendly pest management strategies. [ABSTRACT FROM AUTHOR]

Racial disparities exist in fetal development which in turn can influence growth and development of chronic disease later in life. The purpose of this study was to explore potential racial and ethnic differences in chronic disease risk factors throughout the pediatric years given prenatal exposure to substance use. Data from the Maternal Lifestyle Study cohort was used for this analysis. Urine toxicology confirmed maternal substance use (y/n) and offspring height, weight, and systolic blood pressure (SBP) data at 16 years was analyzed. Linear mixed effects modeling with an interaction term for adolescent race/ethnicity and maternal drug use assessed growth trajectories (body mass index (BMI) percentile) and cardiovascular disease risk factors (elevated SBP). Of the sample (n = 1,388 mother/infant dyads), 23% (n = 319) of mothers used three substances during pregnancy and 14% (n = 200) used four or five. Controlling for BMI, Hispanic adolescents prenatally exposed to any singular substance had 13 mmHg higher SBP at age 16 than their unexposed counterparts (95% Confidence Interval [CI]: 12.24, 14.01). Prenatal exposure to >1 substance significantly lowered SBP in Hispanic adolescents only. Results here showed that Hispanic adolescents exposed to singular substance are at higher risk of elevated SBP in adolescence, but SBP decreased when exposed to >1 substance. The Hispanic paradox may play a role; future studies should continue to explore this. Additionally, barriers to prenatal care for Hispanic women should be addressed in order to prevent substance use during pregnancy which can reduce chronic disease risk in offspring adolescence. [ABSTRACT FROM AUTHOR]

Seventy seven research papers published from 1986 to 2018 were observed. These papers investigated PTEs (Pb, Cd, Cu, As, Fe, Zn, Ni, and total Cr) in leafy (mint, spinach, coriander, and lettuce) and tuberous (potato, carrot, radish, and onion) vegetables irrigated by wastewater. The studies observed in our paper were conducted in 19 countries. The PTEs concentrations were compared among studies and the human health risk was observed. According to the obtained meta-analysis results, PTEs concentrations (mg/kg) in vegetables were found in the following order Zn (34.216)> Cu (22.581)> Ni (14.056)> Pb (10.173)> Cr (8.308)> Fe(8.130)> As(1.881)> Cd (1.763). Hazard index for children was higher than that for adults and for both groups, the calculated HQ was higher than 1, which indicates that there is a health risk for the consumers. This study provides a comprehensive analysis that demonstrates the urgent necessity for treating PTE pollution in agricultural areas worldwide. [ABSTRACT FROM AUTHOR]

Carbazole is an aromatic heterocyclic organic compound consisting of two fused benzene rings and a pyrrole ring and is a very valuable building structure for the design of many compounds for use in various fields of chemistry and medicine. This study presents three new carbazole-based thiazole derivatives that differ in the presence of a different halogen atom: chlorine, bromine, and fluorine. Experimental studies and quantum-chemical simulations show the effect of changing a halogen atom on the physicochemical, biological, and linear and nonlinear optical properties. We have also found that carbazoles C-Cl, C-Br, and C-F exhibit high tyrosinase inhibitory activity, with IC50 values in the range of 68–105 µM with mixed mechanism of action. Finally, molecular docking to the active site of Concanavalin A (ConA) and bioavailability for all compounds were evaluated. [ABSTRACT FROM AUTHOR]

Abstract and ARP Position Statement: Based on the available body of scientific evidence and with the goals of promoting safety of combat sports athletes and striving for the advancement of clean sport, the Association of Ringside Physicians recommends the following regarding cannabis: • Use of marijuana or synthetic cannabinoids by combat sports athletes is discouraged due to unproven benefits and many known adverse effects. Acute use can impair cognition and complex motor function, which likely leads to reduced performance in combat sports. Chronic use can increase risk for heart and lung disease, several cancers, schizophrenia, and can reduce testosterone in men and impair fertility. Benefits from cannabis in most contexts, including athletic performance, have not been proven. • Use of topical purified CBD is neither encouraged nor discouraged. • Since acute cannabis intoxication can impair complex cognitive and motor function, any athlete suspected of acute intoxication at the time of competition – based on clinical judgment – should be banned from that competition. • Wide-scale regulation of cannabis based on quantitative testing has limited usefulness in combat sports, for the following reasons: ∘ Cannabis is not ergogenic and is likely ergolytic. ∘ Concentrations in body fluids correlate poorly with clinical effects and timing of use. ∘ Access to testing resources varies widely across sporting organizations. [ABSTRACT FROM AUTHOR]

Plantain (Musa paradisiaca) has several bioactive components responsible for its pharmacological effects. The present study investigated the comparative antioxidative potential of different plantain part extracts: plantain whole fruit extract (PWFE), plantain pulp extract (PPPE), and plantain peel extract (PPLE) on FeSO₄-induced oxidative stress in isolated rat testes. Oxidative imbalance was induced in the rat testes ex vivo by incubating testis homogenate with 0.1 mM ferrous sulphate (FeSO4) in the presence or absence of plantain extracts at different concentrations (30, 60, 120, and 240 µg/mL) for 30 min at 37 °C. FeSO4 significantly reduced the levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH), while elevating the level of oxidative stress markers like malondialdehyde (MDA). Furthermore, FeSO4 raised the levels of acetylcholine esterase (AChE) and nitric oxide (NO). Moreover, FeSO4 significantly elevated the levels of triglycerides, total cholesterol, low-density lipoprotein (LDL), and very low-density lipoprotein (vLDL), but reduced the level of high-density lipoprotein (HDL). However, PWFE, PPPE, and PPLE improved FeSO4-induced oxidative stress and lipid profiling. In particular, the extracts reduced the cellular concentrations of MDA, NO, AChE, cholesterol, triglycerides, LDL, and vLDL but elevated the levels of GSH, SOD, CAT, and HDL. The results demonstrate the capacity of the different parts of plantain to attenuate FeSO4-induced oxidative injury in rat testes ex vivo. [ABSTRACT FROM AUTHOR]

Both nitric oxide (NO) and nitrogen dioxide (NO2) gasses are toxic to humans but are commonly found in industrial settings such as semiconductor manufacturing sites. Due to the spontaneous oxidation of NO to NO2 under ambient conditions, individuals working with NO may in fact be exposed to both gasses in the case of an accidental release. Unfortunately, most safety materials provided to NO users do not address the potential for associated NO2 toxicity, and, until now, models developed to predict health consequences following a release of NO have not appropriately considered the oxidation kinetics nor the toxicity of both NO and NO2 in their assessments. This paper describes an improved multi‐module model that addresses these limitations and explores whether facilities using NO should consider adopting measures that can mitigate the simultaneous health effects of both gasses. The model predicts the morbidity (intoxication/injury), mortality (death), and treatment outcomes that may arise following an industrial NO release by first calculating the doses of both NO and NO2 received by exposed individuals and then applying newly defined toxicity parameters for NO and NO2 to assign dose‐dependent probabilities for the onset of intoxication and/or death and the ability of appropriate treatment(s) to save lives. Modeling results indicate low risk to worker health in the likeliest release scenarios while identifying less likely situations that carry substantially higher risk. Moreover, these results indicate that risks to worker health can be mitigated with simple measures like maintaining reliable alarms, adequate ventilation, and on‐site supplies of methylene blue, as well as encouraging quick responses by personnel. With appropriate parameterization, the improved modeling framework is generalizable to any chemical release, especially multi‐hazard releases resulting from the conversion of one toxic compound into another under likely environmental conditions. By directly addressing the toxicities of multiple compounds, the improved model presents a more realistic picture of the potential health consequences of a chemical release. This generalizable framework for modeling of multi‐hazard chemical releases can inform preparedness and risk mitigation strategies for NO release events. Given the spontaneous oxidation of NO to NO2 under ambient conditions, individuals working with NO in industrial contexts may be exposed to both NO and NO2. This paper describes an improved multi‐module model that considers facility ventilation, oxidation kinetics, and the toxicity of both NO and NO2 and applies the model to explore whether facilities using NO should consider adopting measures that can mitigate the potential for adverse health effects from both gasses during a NO release. [ABSTRACT FROM AUTHOR]

Megaloptera larvae are important bioindicator species and potential resource insects. To further cultivate their economic role, their living environment must be examined in more detail. In this study, we analyzed the physiological and biochemical effects of a sublethal dose of imidacloprid, a widely used neonicotinoid insecticide, on the larvae of Protohermes xanthodes. After treatment with imidacloprid, P. xanthodes larvae exhibited clear symptoms of poisoning, including the head curling up toward the ventral surface. Additionally, the activity of acetylcholinesterase was significantly inhibited following exposure. The activities of glutathione S-transferases initially continuously increased but showed a slight decrease after 8 days. Catalase activity initially increased and then decreased following imidacloprid treatment; superoxide dismutase activity fluctuated over time, and peroxidase activity continuously increased. The expression levels of HSP70s genes were evaluated using qRT-PCR. These results indicate that P. xanthodes larvae exhibit a toxic response to imidacloprid exposure, manifested as oxidative stress, as observed through behavioral and physiological indicators. [ABSTRACT FROM AUTHOR]

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Two-spotted spider mite (Tetranychus urticae Koch, 1836, Acari: Tetranychidae) causes significant yield losses in cultivated plants, especially depending on the season. Chemical methods are the main methods of controlling this pest. However, besides the environmental, human, and animal health problems arising from chemical control, adverse effects such as resistance and residues limit the success and sustainability of chemical control. This experiment was conducted in the applied acarology laboratory of the Directorate of Plant Protection Central Research Institute in Ankara, Türkiye, in incubators maintained at 25 ± 1 °C temperature, 50–65% humidity, and 16 L: 8 D h photoperiod. In this study, the potential acaricidal effect of aqueous extracts of Morus rubra, Daphne odora, Ficus carica, Matricaria chamomilla, and Mentha pulegium collected from Ankara and Adana provinces on T. urticae was investigated. For this purpose, the leaves of the plants were dried and ground and 1%, 3%, 6%, and 12% concentrations (w/v) of the extracts obtained were tested in three different application periods (1–6 day). Dipping and spraying methods were used to determine mortality and toxicity. The highest effect was 94.4% at the end of the 6th day at a 12% concentration of M. pulegium in the dipping method. On the other hand, the lowest mortality effect was 18.2% at the same time and concentration of M. chamomilla. In lethal toxicity studies, the highest toxicity was obtained from F. carica with an LC50 value of 4756 mg L−1, and the lowest toxicity was obtained from D. odora with an LC50 value of 12,417 mg L−1. We believe that plant extracts provide a valid alternative in effectively controlling two-spotted spider mites, reducing the need for pesticide use and minimizing residues. [ABSTRACT FROM AUTHOR]

The European Commission asked EFSA to update its 2012 risk assessment on brominated phenols and their derivatives in food, focusing on five bromophenols and one derivative: 2,4,6‐tribromophenol (2,4,6‐TBP), 2,4‐dibromophenol (2,4‐DBP), 4‐bromophenol (4‐BP), 2,6‐dibromophenol (2,6‐DBP), tetrabrominated bisphenol S (TBBPS), tetrabromobisphenol S bismethyl ether (TBBPS‐BME). Based on the overall evidence, the CONTAM Panel considered in vivo genotoxicity of 2,4,6‐TBP to be unlikely. Effects in liver and kidney were considered as the critical effects of 2,4,6‐tribromophenol (2,4,6‐TBP) in studies in rats. A BMDL10 of 353 mg/kg body weight (bw) per day for kidney papillary necrosis in male rats was identified and was selected as the reference point for the risk characterisation. The derivation of a health‐based guidance value was not considered appropriate due to major limitations in the toxicological database. Instead, the margin of exposure (MOE) approach was applied to assess possible health concerns. Around 78,200 analytical results for 2,4,6‐TBP in food were used to estimate dietary exposure for the European population. Considering the resulting MOE values, all far above an MOE of 6000 that does not raise a health concern, and accounting for the uncertainties affecting the exposure and hazard assessments, the CONTAM Panel concluded with at least 95% probability that the current dietary exposure to 2,4,6‐TBP does not raise a health concern. Due to lack of occurrence data, no risk assessment could be performed for breastfed or formula‐fed infants. No risk characterisation could be performed for any of the other brominated phenols and derivatives included in the assessment, due to lack of data both on the toxicity and occurrence. [ABSTRACT FROM AUTHOR]

Background: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients. Methods: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, 'eventful admission', was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital. Results: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273). Conclusions: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. Trial registration: OSF registration ID: osf.io/7e5uy. [ABSTRACT FROM AUTHOR]

Cancer prevention is currently envisioned as a molecular-based approach to prevent carcinogenesis in pre-cancerous stages, i.e., dysplasia and carcinoma in situ. Cancer is the second-leading cause of mortality worldwide, and a more than 61% increase is expected by 2040. A detailed exploration of cancer progression pathways, including the NF-κβ signaling pathway, Wnt-B catenin signaling pathway, JAκ-STAT pathway, TNF-α-mediated pathway, MAPκ/mTOR pathway, and apoptotic and angiogenic pathways and effector molecules involved in cancer development, has been discussed in the manuscript. Critical evaluation of these effector molecules through molecular approaches using phytomolecules can intersect cancer formation and its metastasis. Manipulation of effector molecules liκe NF-κβ, SOCS, β-catenin, BAX, BAκ, VEGF, STAT, Bcl2, p53, caspases, and CDκs has played an important role in inhibiting tumor growth and its spread. Plant-derived secondarymetabolites obtained fromnatural sources have been extensively studied for their cancer-preventing potential in the last few decades. Eugenol, anethole, capsaicin, sanguinarine, EGCG, 6-gingerol, and resveratrol are some examples of such interesting lead molecules and are mentioned in the manuscript. This worκ is an attempt to put forward a comprehensive approach to understanding cancer progression pathways and their management using effector herbal molecules. The role of different plant metabolites and their chronic toxicity profiling in modulating cancer development pathways has also been highlighted. [ABSTRACT FROM AUTHOR]

Background: Metabolomics is the study of metabolites in cells, tissues, live organisms, and biological fluids to elucidate their composition and possible roles. Metabolomics and its biomarkers have emerged as a powerful tool for evaluating the efficacy of probiotics in various pathological conditions, including toxicological settings. This review explores the use of metabolomics-based markers to assess the safety and efficacy of probiotics in toxicological settings. Result: This review aims to determine biomarkers for measuring the effectiveness of probiotic therapies in toxicological contexts based on exposure, effects, susceptibility, prognostic, and therapeutic biomarkers. In this study, 1979 articles were systematically searched in PubMed (PM), Scopus (Sc), Google Scholar (GS), and Web of Science (WOS) between the years 2013 and 2023 inclusive using keywords, inclusion, and exclusion criteria. The result showed that 1439 human samples were used from 2013 to 2023 publications with the UK having the highest number of publications, data, and sample types in 2023. Again, the result showed most of the publications are on susceptibility-based biomarkers. Conclusion: Metabolomics-based biomarkers may provide insight into metabolism-related alterations related to probiotic therapies while clarifying their biological mechanisms, especially in toxicology enabling specific probiotic therapy. [ABSTRACT FROM AUTHOR]

The present study explores the synthesis and bio-safety evaluation of gadolinium-doped carbon quantum dots (GCQDs) as a potential dual-contrast agent for diagnostic imaging. GCQDs exhibit both fluorescent and magnetic properties, making them suitable for UV–Vis and magnetic resonance imaging (MRI). The synthesis of GCQDs was achieved via hydrothermal treatment, incorporating gadolinium into the carbon quantum dot matrix. The magnetic properties of GCQDs were analyzed, showing significantly enhanced values compared to gadobutrol, a common MRI contrast agent. However, synthesis constraints limit the gadolinium content achievable in nanodots. To assess the safety of GCQDs, their effects on the embryonic development of zebrafish (Danio rerio) were examined. Various concentrations of GCQDs were tested, observing mortality rates, hatchability, malformations, heartbeats, spontaneous movement, and GCQDs uptake. Dialysis studies indicated that gadolinium ions are incorporated into the internal structure of the carbon nanodots. Zebrafish toxicity tests revealed that while survival rates were comparable to control groups, hatchability decreased significantly with higher gadolinium concentrations in GCQDs. Fluorescence microscopy showed no statistical differences in the fluorescence intensity between groups. These findings suggest that GCQDs could serve as an effective dual-contrast agent, combining the optical imaging capabilities of CQDs with the enhanced MRI contrast provided by gadolinium. This study underscores the need for further research on the synthesis methods and biological interactions of GCQDs to ensure their safety and efficacy in medical applications. [ABSTRACT FROM AUTHOR]

In recent years, advances in nanotechnology have significantly influenced electronics manufacturing, industrial processes, and medical research. Various industries have seen a surge in the use of nanomaterials. However, several researchers have raised the alarm about the toxicological nature of nanomaterials, which appear to be quite different from their crude forms. This altered nature can be attributed to their unique physicochemical profile. They can adversely affect human health and the environment. Nanomaterials that have been released into the environment tend to accumulate over time and can cause a significant impact on the ecosystem and organisms with adverse health effects. Increased use of nanoparticles has led to increased human exposure in their daily lives, making them more vulnerable to nanoparticle toxicity. Because of their small size, nanomaterials can readily cross biological membranes and enter cells, tissues, and organs. Therefore, the effect of nanomaterials on the human environment is of particular concern. The toxicological effects of nanomaterials and their mechanisms of action are being researched worldwide. Technological advances also support monitoring new nanomaterials marketed for industrial and household purposes. It is a challenging area because of the exceptional physicochemical properties of nanomaterials. This updated review focuses on the diverse toxicological perspective of nanomaterials. We have discussed the use of different types of nanoparticles and their physiochemical properties responsible for toxicity, routes of exposure, bio-distribution, and mechanism of toxicity. The review also includes various in vivo and in vitro methods of assessing the toxicity of nanomaterials. Finally, this review will provide a detailed insight into nano material-induced toxicological response, which can be beneficial in designing safe and effective nanoparticles. [ABSTRACT FROM AUTHOR]

Tattoo pigment is expected to migrate beyond the skin to regional lymph nodes and the liver. Modern tattoo ink commonly contains metals that may pose a clinical problem during MRI examinations. This study aimed to investigate the biodistribution of iron oxide pigment to internal organs in mice. Moreover, when exposed to a static magnetic field, we studied whether any reactions followed in the tattooed skin. Twenty‐seven hairless C3.Cg‐Hrhr/TifBomTac mice were included; 20 were tattooed with iron oxide ink in a rectangular 3 cm2 pattern; seven were controls. Ten of the tattooed mice were exposed to a 3 T MRI scanner's static magnetic field. Following euthanasia, evaluations of dissected organs involved MRI T2*‐mapping, light microscopy (LM) and metal analysis. T2*‐mapping measures the relaxation times of hydrogen nuclei in water and fat, which may be affected by neighbouring ferrimagnetic particles, thus enabling the detection of iron oxide particles in organs. Elemental analysis detected a significant level of metals in the tattooed skin compared to controls, but no skin reactions occurred when exposed to a 3 T static magnetic field. No disparity was observed in the liver samples with metal analysis. T2* mapping found no significant difference between the two groups. Only minute clusters of pigment particles were observed in the liver by LM. Our results demonstrate a minimal systemic distribution of the iron oxide pigments to the liver, whereas the kidney and brain were unaffected. The static magnetic field did not trigger skin reactions in magnetic tattoos but may induce image artefacts during MRI. [ABSTRACT FROM AUTHOR]

One of the many unresolved obstacles in the field of cardiovascular research is an uncompromising in vitro cardiac model. While primary cell sources from animal models offer both advantages and disadvantages, efforts over the past half-century have aimed to reduce their use. Additionally, obtaining a sufficient quantity of human primary cardiomyocytes faces ethical and legal challenges. As the practically unlimited source of human cardiomyocytes from induced pluripotent stem cells (hiPSC-CM) is now mostly resolved, there are great efforts to improve their quality and applicability by overcoming their intrinsic limitations. The greatest bottleneck in the field is the in vitro ageing of hiPSC-CMs to reach a maturity status that closely resembles that of the adult heart, thereby allowing for more appropriate drug developmental procedures as there is a clear correlation between ageing and developing cardiovascular diseases. Here, we review the current state-of-the-art techniques in the most realistic heart models used in disease modelling and toxicity evaluations from hiPSC-CM maturation through heart-on-a-chip platforms and in silico models to the in vitro models of certain cardiovascular diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND: Significant progress has been made over the past decade in measuring the chemical components of the exposome, providing transformative population-scale frameworks in probing the etiologic link between environmental factors and disease phenotypes. While the analytical technologies continue to evolve with reams of data being generated, there is an opportunity to complement exposome-wide association studies (ExWAS) with functional analyses to advance etiologic search at organismal, cellular, and molecular levels. OBJECTIVES: Exposomics is a transdisciplinary field aimed at enabling discovery-based analysis of the nongenetic factors that contribute to disease, including numerous environmental chemical stressors. While advances in exposure assessment are enhancing population-based discovery of exposome-wide effects and chemical exposure agents, functional screening and elucidation of biological effects of exposures represent the next logical step toward precision environmental health and medicine. In this work, we focus on the use, strategies, and prospects of alternative approaches and model systems to enhance the current human exposomics framework in biomarker search and causal understanding, spanning from bench-based nonmammalian organisms and cell culture to computational new approach methods (NAMs). DISCUSSION: We visit the definition of the functional exposome and exposomics and discuss a need to leverage alternative models as opposed to mammalian animals for delineating exposome-wide health effects. Under the “three Rs” principle of reduction, replacement, and refinement, model systems such as roundworms, fruit flies, zebrafish, and induced pluripotent stem cells (iPSCs) are advantageous over mammals (e.g., rodents or higher vertebrates). These models are cost-effective, and cell-specific genetic manipulations in these models are easier and faster, compared to mammalian models. Meanwhile, in silico NAMs enhance hazard identification and risk assessment in humans by bridging the translational gaps between toxicology data and etiologic inference, as represented by in vitro to in vivo extrapolation (IVIVE) and integrated approaches to testing and assessment (IATA) under the adverse outcome pathway (AOP) framework. Together, these alternatives offer a strong toolbox to support functional exposomics to study toxicity and causal mediators underpinning exposure–disease links. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd‐exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd‐exposed rats had increased liver cholesterol levels, insulin receptor beta (IRβ) and peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats. [ABSTRACT FROM AUTHOR]

A 12-week-old, female, entire miniature dachshund presented with a 3-week history of progressive vulval enlargement with an associated clear serous sanguinolent discharge. Vulval oedema was noted on clinical exam. Further investigations included a complete cell count, computer tomography and a guarded vaginal swab, which revealed vaginal epithelial cell keratinisation. After thorough anamnesis, the clinical signs were concluded to be a result of exogenous oestrogen exposure. [ABSTRACT FROM AUTHOR]

The advancement of medical toxicology knowledge has traditionally relied on case reports and case series because of the ethical challenges involved in studying poisoned patients. The growing availability of several large databases and registries now allows researchers to describe and analyze patterns in poisoned patients who share a particular exposure, outcome, or condition. A large database or registry can be useful in generating hypotheses, supporting extramural funding applications, and planning more rigorous studies. Knowing how to access and interpret data in registries such as NPDS, NHAMCS, and HCUP is essential for all stakeholders engaged in medical toxicology research. This review describes the strengths and limitations of different toxicology-relevant registries and databases and how to leverage these powerful tools to advance the science in the field of medical toxicology. [ABSTRACT FROM AUTHOR]

The Toxicology Investigators Consortium (ToxIC) was launched as a prospective multi-center registry of cases who receive medical toxicology consultations. Now, with over 100,000 cases, the Core Registry continues to address many medical toxicology research questions and has served as the foundation for multiple sub-registries, including the North American Snakebite Registry and the Medications for Opioid Use Disorder sub-registry. ToxIC also has evolved a portfolio of non-registry-based projects utilizing medical toxicology physician site principal investigators who enroll patients through emergency departments, irrespective of whether they received a medical toxicology consultation. These studies include the FDA-ACMT COVID-19 ToxIC Pharmacovigilance Project, which identifies adverse drug reactions related to the treatment of COVID-19, the Fentalog Study a toxico-surveillance study of suspected opioid overdose cases, the Drug Overdose Toxico-Surveillance Reporting Program which enrolls either suspected stimulant or opioid overdose cases, and the just being launched Real-World Examination of Naloxone for Drug Overdose Reversal project. Given ToxIC's experience in multi-center studies and its well-developed infrastructure, it is well-positioned to provide a nimble response on the part of the medical toxicology community to addressing evolving toxicological threats, drug and chemical toxicosurveillance, and other important medical toxicology priorities. [ABSTRACT FROM AUTHOR]

Background: Co-use of stimulants and opioids is often deliberate. However, the possibility remains that some people are unintentionally consuming fentanyl. To advance understanding of overdose risk, we examined the rate of concordance between self-reported fentanyl use and corresponding urine toxicology screen results. Methods: Between August 2022–August 2023, 411 participants (adults who reported any non-medical drug use in the past three months) in Nevada and New Mexico completed a cross-sectional survey, of whom 64% (n = 270; the analytical sample) also completed a urine toxicology screen, which detects fentanyl use in the past three days. Positive predictive value, negative predictive value, sensitivity, and specificity were calculated using self-reported past three-day fentanyl use (yes/no) and urine toxicology screen results for the presence of fentanyl (positive/negative). Results: Of the 270 participants who provided a urine sample, 268 are included in the descriptive statistics (two with inconclusive urine toxicology screen results were excluded). Of the 268 participants, 146 (54.5%) had a fentanyl-positive urine toxicology screen result, 122 (45.5%) had a fentanyl-negative urine toxicology screen result, 137 (51.1%) reported past three-day fentanyl use, and 130 (48.5%) reported no past three-day fentanyl use. Only 6.9% of those with a fentanyl-positive urine toxicology screen did not report recent fentanyl use. The sensitivity of self-reported fentanyl use was 93%, specificity was 97%, positive predictive value was 97%, and negative predictive value was 92%. Discussion: The rate of unanticipated exposure to fentanyl (that is, positive urine screen and negative self-report) in this sample was low, at 6.9%. This runs counter to the national narrative that there is widespread unknown contamination of fentanyl in the drug supply. Conclusion: Future research is needed to further explore how people who use multiple substances interpret their overdose risk and what harm reduction methods they employ. [ABSTRACT FROM AUTHOR]

Introduction: Chlorine and chloramine gas inhalation can occur when household cleaners are mixed. The increased emphasis on disinfecting practices during the COVID-19 pandemic may have contributed to an increase in chlorine and chloramine gas exposures in the United States, which has not been studied. Methods: In a retrospective review, reported data on chlorine and chloramine gas exposures in the National Poison Data System were collected from January 1, 2015, to December 31, 2022. Data included demographics and exposure details, including location, dose, formulation, co-exposures, treatments, and outcomes. Demographic analyses and descriptive statistics were conducted. Results: During the study period, 85,104 total exposures to chlorine and chloramine gas were reported, consisting of 79,281 isolated exposures and 5,823 co-exposures. Total exposures increased by 61% from 8,385 in 2015 to 13,503 in 2022, with the largest increase of 38.3% occurring from 2019 to 2020. Total exposures remained increased through 2022 with no return to pre-pandemic levels. Most exposures occurred in "own residence" (n = 72,213, 84.9%), with a larger proportion of exposures occurring at home peri-pandemic versus pre-pandemic (88.4% versus 81.7%). One percent (n = 1,030) of exposures were admitted to a non-critical care unit, 0.73% (n = 619) were admitted to a critical care unit, and 0.03% (n = 26) resulted in death. Discussion: The onset of the COVID-19 pandemic and increased emphasis on cleaning practices were likely contributing factors to the marked increase in exposures in 2020, which persisted through 2022. Cleaning practices that developed during the beginning of the pandemic likely persisted despite returning to more normal daily routines, which may explain the ongoing increase in reported exposures. Most reported exposures were unintentional, mild in symptomatology, and required the use of non-invasive therapies, if any. Conclusions: Future efforts should focus on public education on the safe use of cleaning products to prevent exposure to toxic chlorine and chloramine gases. [ABSTRACT FROM AUTHOR]

Introduction: Tricyclic antidepressants often cause drug-induced QRS complex prolongation in overdose but are now less commonly prescribed. We sought to determine, among a contemporary cohort of patients, the pharmaceuticals independently associated with QRS complex prolongation in acute overdose. Methods: We performed secondary analysis of data from the Toxicology Investigators Consortium (ToxIC) Core Registry. We included adult patients presenting from January 2016 through March 2023 with acute or acute-on-chronic pharmaceutical exposures. The primary outcome was QRS complex prolongation >0.12 s. Secondary outcomes included cardiac arrest, death, ventricular dysrhythmia, intensive care unit admission, initiation of vasopressors, and treatment with sodium bicarbonate. We used a multivariable logistic regression model with QRS complex prolongation as the outcome and individual pharmaceuticals of interest as independent variables. We assessed yearly trends of the contribution of relevant pharmaceuticals to QRS complex prolongation since 2016. Results: Of 11,945 patients in the total cohort (median age 37 years, 6,652 [55.7%] female), 366 (3.1%) developed QRS complex prolongation. Of 9,417 patients included in the model, 290 (3.1%) developed QRS complex prolongation. Amitriptyline, nortriptyline, doxepin, imipramine, noxiptiline, bupropion, flecainide, carvedilol, propranolol, diphenhydramine, and lamotrigine poisonings were independent predictors of QRS complex prolongation. Flecainide poisoning conferred the greatest odds of QRS complex prolongation (OR 574.1; 95% CI: 88.3–12,747). The contribution of tricyclic antidepressants to QRS complex prolongation decreased from 38.8% to 17.6% of all patients with QRS complex prolongation from 2016 to 2022. In 2022, the proportion of QRS complex prolongation from diphenhydramine (20.6%) surpassed that of tricyclic antidepressants. Discussion: This study provides insights into contemporary pharmaceutical poisoning associated with QRS complex prolongation. Tricyclic antidepressants remain clinically relevant exposures but are no longer the most common cause of drug-induced QRS complex prolongation. Conclusions: Bupropion, diphenhydramine, and antidysrhythmics are increasingly common causes of QRS complex prolongation, each associated with numerous severe outcomes in poisoning. Greater safety measures to protect patients from cardiovascular toxicity from these pharmaceuticals are warranted. [ABSTRACT FROM AUTHOR]

Boldine is a plant-derived bioactive compound that has a beneficial impact on human health. Boldine is an aporphine alkaloid mainly obtained from the leaves and bark of the Chilean Boldo tree (Peumus boldus, Family: Monimiaceae). There are plenty of preclinical evidence supports that boldine exerts its beneficial effects against various diseases. Lumiskin™, a patented and marketed formulation by Revitol Skincare for skin brightening, contains Dicetyl boldine, a boldine derivative. All the available information on the Chilean boldo tree (P. boldus Molina) species was actualized by systematically searching the scientific databases (PubMed, SciFinder, Web of Science, Google Scholar, Scopus and others) and scientific literature. This article covers the recent advances in pharmacokinetic, toxicological, pharmacological/biological activities, and molecular mechanisms of the bioactive compound to understand health benefits of boldine better. Boldine exerts antioxidant, hepatoprotective, anti-atherosclerotic, anti-diabetic, analgesic, antipyretic, anti-inflammatory, anti-epileptic, neuroprotective, nephroprotective, anti-arthritis, anticancer and nootropic effects. Moreover, boldine exhibits its various pharmacological activities by altering antioxidant parameters (MDA, superoxide dismutase, glutathione), peroxynitrite, inflammatory markers apoptotic index, caspase-3, acetyl-cholinesterase, myeloperoxidase, TNF-α (Tumor necrosis factor-α), iNOS, Bcl-2-associated X protein (BAX), ACE-1(Angiotensin-converting enzyme-1), dopamine D2 receptors and nicotinic acetylcholine receptor. Boldine has the potential to modulate a variety of biological networks. Due to its versatile pharmacological effects reported in various experimental animals as well as in randomized clinical trials for the treatment of facial melasma and for treatment of urinary stone lithotripsy in children as a complementary phytotherapy; in the future, this compound might be developed as a novel drug for a different indication [ABSTRACT FROM AUTHOR]