Search Results (41,881)

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a single mutation in the huntingtin gene (HTT). Normal HTT has a CAG trinucleotide repeat at its N-terminal within the range of 36. However, once the CAG repeats exceed 37, the mutant gene (mHTT) will encode mutant HTT protein (mHTT), which results in neurodegeneration in the brain, specifically in the striatum and other brain regions. Since the mutation was discovered, there have been many research efforts to understand the mechanism and develop therapeutic strategies to treat HD. HTT is a large protein with many post-translational modification sites (PTMs) and can be modified by phosphorylation, acetylation, methylation, sumoylation, etc. Some modifications reduced mHTT toxicity both in cell and animal models of HD. We aimed to find the known kinase inhibitors that can modulate the toxicity of mHTT. We performed an in vitro kinase assay using HTT peptides, which bear different PTM sites identified by us previously. A total of 368 kinases were screened. Among those kinases, cyclin-dependent kinases (CDKs) affected the serine phosphorylation on the peptides that contain S1181 and S1201 of HTT. We explored the effect of CDK1 and CDK5 on the phosphorylation of these PTMs of HTT and found that CDK5 modified these two serine sites, while CDK5 knockdown reduced the phosphorylation of S1181 and S1201. Modifying these two serine sites altered the neuronal toxicity induced by mHTT. Roscovitine, a CDK inhibitor, reduced the p-S1181 and p-S1201 and had a protective effect against mHTT toxicity. We further investigated the feasibility of the use of roscovitine in HD mice. We confirmed that roscovitine penetrated the mouse brain by IP injection and inhibited CDK5 activity in the brains of HD mice. It is promising to move this study to in vivo for pre-clinical HD treatment. Full article

Kraits are venomous snakes of the genus Bungarus from the family Elapidae. Their venom typically demonstrates neurotoxicity; however, the toxicity is significantly influenced by the snake’s species and geographical origin. Among the Bungarus species, Bungarus suzhenae and B. bungaroides have been poorly studied, with little to no information available regarding their venom composition. In this study, a proteomic approach was employed using LC-MS/MS to identify proteins from trypsin-digested peptides. The analysis revealed 102 venom-related proteins from 18 distinct functional protein families in the venom of B. suzhenae, with the primary components being three-finger toxins (3-FTx, 25.84%), phospholipase A₂ (PLA₂, 40.29%), L-amino acid oxidase (LAAO, 10.33%), Kunitz-type serine protease inhibitors (KUN, 9.48%), and snake venom metalloproteinases (SVMPs, 6.13%). In the venom of B. bungaroides, 99 proteins from 17 families were identified, with primary components being 3-FTx (33.87%), PLA₂ (37.91%), LAAO (4.21%), and KUN (16.60%). Enzymatic activity assays confirmed the presence of key venom enzymes. Additionally, the LD50 values for B. suzhenae and B. bungaroides were 0.0133 μg/g and 0.752 μg/g, respectively, providing a reference for toxicity studies of these two species. This research elucidates the proteomic differences in the venoms of these two species, offering a foundation for developing antivenoms and clinical treatments for envenomation. Full article

The aim of this article is to analyse the global environmental impact of wind farms, i.e., the effects on human health and the local ecosystem. Compared to conventional energy sources, wind turbines emit significantly fewer greenhouse gases, which helps to mitigate global warming. During the life cycle of a wind farm, 86% of CO₂ emissions are generated by the extraction of raw materials and the manufacture of wind turbine components. The water consumption of wind farms is extremely low. In the operational phase, it is 4 L/MWh, and in the life cycle, one water footprint is only 670 L/MWh. However, wind farms occupy a relatively large total area of 0.345 ± 0.224 km²/MW of installed capacity on average. For this reason, wind farms will occupy more than 10% of the land area in some EU countries by 2030. The impact of wind farms on human health is mainly reflected in noise and shadow flicker, which can cause insomnia, headaches and various other problems. Ice flying off the rotor blades is not mentioned as a problem. On a positive note, the use of wind turbines instead of conventionally operated power plants helps to reduce the emission of particulate matter 2.5 microns or less in diameter (PM 2.5), which are a major problem for human health. In addition, the non-carcinogenic toxicity potential of wind turbines for humans over the entire life cycle is one of the lowest for energy plants. Wind farms can have a relatively large impact on the ecological system and biodiversity. The destruction of animal migration routes and habitats, the death of birds and bats in collisions with wind farms and the negative effects of wind farm noise on wildlife are examples of these impacts. The installation of a wind turbine at sea generates a lot of noise, which can have a significant impact on some marine animals. For this reason, planners should include noise mitigation measures when selecting the site for the future wind farm. The end of a wind turbine’s service life is not a major environmental issue. Most components of a wind turbine can be easily recycled and the biggest challenge is the rotor blades due to the composite materials used. Full article

It is imperative to comprehend the mechanisms that underlie drug toxicity in order to enhance the efficacy and safety of novel therapeutic agents. The capacity to identify molecular pathways that contribute to drug-induced toxicity has been significantly enhanced by recent developments in omics technologies, such as transcriptomics, proteomics, and metabolomics. This has enabled the early identification of potential adverse effects. These insights are further enhanced by computational tools, including quantitative structure–activity relationship (QSAR) analyses and machine learning models, which accurately predict toxicity endpoints. Additionally, technologies such as physiologically based pharmacokinetic (PBPK) modeling and micro-physiological systems (MPS) provide more precise preclinical-to-clinical translation, thereby improving drug safety assessments. This review emphasizes the synergy between sophisticated screening technologies, in silico modeling, and omics data, emphasizing their roles in reducing late-stage drug development failures. Challenges persist in the integration of a variety of data types and the interpretation of intricate biological interactions, despite the progress that has been made. The development of standardized methodologies that further enhance predictive toxicology is contingent upon the ongoing collaboration between researchers, clinicians, and regulatory bodies. This collaboration ensures the development of therapeutic pharmaceuticals that are more effective and safer. Full article

Background: To date, the only potential curative treatment for multiple myeloma (MM) remains allogeneic (allo) hematopoietic cell transplant (HCT), although, most patients will eventually relapse. In relapsed patients, donor lymphocyte infusions (DLIs) have been reported to control disease, but the optimal strategy prior to and doses of DLIs remain unclear. With this study (NCT03413800), we aimed to investigate the efficacy and toxicity of lenalidomide and dexamethasome (Len/Dex) followed by escalating pre-determined doses of DLIs in MM patients who relapsed after allo HCT. Methods: Patients aged 18–65 years with relapsed MM following upfront tandem autologous (auto)/allo HCT were eligible. Treatment consisted of six cycles of Len/Dex followed by three standardized doses of DLIs: 5 × 10⁶ CD3+/kg, 1 × 10⁷/kg and 5 × 10⁷/kg every 6 weeks. Bone marrow minimal measurable disease (MRD) using flow cytometry (10⁻⁵) was performed at enrolment, then every 3 months for 2 years or until disease progression, in a subset of patients. The primary endpoint was efficacy as measured by progression-free survival (PFS) at 2 years following Len/Dex/DLIs. Secondary objectives were safety including GVHD, response including MRD status and overall survival (OS). Results: A total of 22 patients participated in this study, including 62% with high-risk cytogenetics. With a median follow-up of 5.3 years (range: 4.1–6.1), PFS and OS were 26.5% (95% CI: 10.4–45.9%) and 69.2% (95% CI: 43.3–85.1%), respectively. Overall, the best responses achieved post-Len/Dex + DLIs were complete remission in 9.1%, very good partial response in 50%, and progressive disease in 40.9%. Among the nine patients tested for MRD, only two achieved a negative status after receiving DLIs. Six patients died, all due to disease progression. No acute GVHD was observed after DLIs. We report a very low incidence of moderate/severe chronic GVHD of 18.2% with no need for systemic immunosuppressants one year after diagnosis. No unexpected adverse events were observed. Interestingly, a positive correlation between response to Len/Dex re-induction and response to DLIs was found (p = 0.0032). Conclusions: Our findings suggest that Len/Dex/DLIs in second line treatment after upfront tandem auto/allo HCT in relapsed MM patients remains feasible and safe. With a potential correlation between induction chemotherapy and DLI responses, more potent induction regimens together with higher doses of DLIs should be considered in the future. Full article

Dissolved organic matter (DOM), primarily in the form of humic acid (HA), plays a crucial role in trace metal (TM) speciation and their subsequent adsorption dynamics on microplastics (MP) in aquatic environments. This study evaluates the impact of environmentally relevant concentrations of HA on the adsorption behaviors of essential (Co, Cu, Ni, and Zn) and toxic (Cd and Pb) TMs onto polyethylene (PE) and polypropylene (PP) pellets, as well as PP fibers under marine conditions, during a six-week experiment. The HA concentrations were 0.1, 1, and 5 mg/L, while all metals were in the same amounts (10 µg/L). Results reveal that HA significantly influences the adsorption of Cu, Pb, and Zn on MP, particularly on PP fibers, which exhibited the greatest TM adsorption dynamics. The adsorption patterns correspond to the concentrations of these metals in seawater, with the sequence for pellets being Zn > Cu > Pb > Ni > Co~Cd, and for fibers Cu > Zn > Pb > Co~Ni > Cd. Speciation modeling supported these findings, indicating that Cu, Pb, and Zn predominantly associate with HA in seawater, facilitating their adsorption on MP, whereas Cd, Co, and Ni mainly form free ions and inorganic complexes, resulting in slower adsorption dynamics. Statistical analysis confirmed the influence of HA on the adsorption of Cd, Pb, Cu, and Ni. By investigating the dynamics of TM adsorption on plastics, the influence of DOM on these two contaminants under marine conditions was evaluated. The presented results can help in forming a better understanding of synergistic plastic and trace metal pollution in marine systems that are relevant at the global level, since both contaminants pose a serious threat to aquatic ecosystems. Full article

Abstract: The use of organic solvents, particularly those of a non-polar nature, is a common practice during cleaning operations in the restoration of polychrome artworks and metallic artifacts. However, these solvents pose significant risks to the health of operators and the environment. This study explores the formulation of innovative gels based on non-polar solvents and cellulose derivatives, proposing a safe and effective method for cleaning metallic artworks. The study is focused on a toxic apolar solvent, Ligroin, identified as one of the most widely used solvents in the cultural heritage treatments, and some “green” alternatives such as Methyl Myristate and Isopropyl Palmitate. The main challenge lies in overcoming the chemical incompatibility between non-polar solvents and polar thickening agents like cellulose ethers. To address this problem, the research was based on a hydrophilic–lipophilic balance (HLB) system and Hansen solubility parameters (HSPs) to select appropriate surfactants, ensuring the stability and effectiveness of the formulated gels. Stability, viscosity, and solvent release capacity of gels were analyzed using Static Light Multiple Scattering (Turbiscan), viscometry, and thermogravimetric analysis (TGA). The efficacy of cleaning in comparison with Ligroin liquid was evaluated on a metal specimen treated with various apolar protective coatings used commonly in the restoration of metallic artifacts, such as microcrystalline waxes (Reswax, Soter), acrylic resins (Paraloid B44), and protective varnishes (Incral, Regalrez). Multispectral analysis, digital optical microscopy, FTIR spectroscopy, and spectrocolorimetry allowed for the assessment of the gels’ ability to remove the different protective coatings, the degree of cleaning achieved, and the presence of any residues. The results obtained highlight the ability of the formulated gels to effectively remove protective coatings from metallic artifacts. Cetyl Alcohol proved to be the most versatile surfactant to realize a stable and efficient gel. The gels based on Methyl Myristate and Isopropyl Palmitate showed promising results as “green” alternatives to Ligroin, although in some cases, they exhibited less selectivity in the removal of protective coatings. Full article

This study focuses on the physiological response of lettuce grown on Technosols designed for the remediation of soils polluted by potentially harmful elements (PHEs: As, Cd, Cu, Fe, Pb, and Zn). Lettuce plants were grown in five treatments: recovered (RS) and polluted soil (PS) as controls, and three Technosols (TO, TS, and TV) consisting of 60% PS mixed with 2% iron sludge, 20% marble sludge, and 18% organic wastes (TO: composted olive waste, TS: composted sewage sludge, and TV: vermicompost of garden waste). The main soil properties and PHE solubility were measured, together with physiological parameters related to phytotoxicity in lettuce such as growth, photosynthetic capacity, oxidative stress, and antioxidant defence. All Technosols improved unfavourable conditions of PS (i.e., neutralised acidity and enhanced OC content), leading to a significant decrease in Cd, Cu, and Zn mobility. Nevertheless, TV was the most effective as the reduction in PHEs mobility was higher. Furthermore, lettuce grown on TV and TO showed higher growth (+90% and +41%) than PS, while no increase in TS. However, lower oxidative stress and impact on photosynthetic rate occurred in all Technosols compared to PS (+344% TV, +157% TO, and +194% TS). This physiological response of lettuce proves that PHE phytotoxicity is reduced by Technosols. Thus, this ecotechnology constitutes a potential solution for soil remediation, with effectiveness of Technosols depending largely on its components. Full article

Overexposure to ultraviolet radiation mainly leads to skin disorders (erythema, burns, immunosuppression), skin aging, and skin cancer as the most serious side effect. It has been widely accepted that using sunscreen products is an important way to protect against the harmful effects of UV rays. Although commercial sunscreens have constantly changed and improved over time, there are emerging concerns about the safety of conventional, organic, UV filters due to adverse effects on humans (such as photoallergic dermatitis, contact sensitivity, endocrine-disrupting effects, etc.) as well as accumulation in the environment and aquatic organisms. This is why natural compounds are increasingly being investigated and used in cosmetic and pharmaceutical sunscreens. Some of these compounds are widely available, non-toxic, safer for use, and have considerable UV protective properties and less side effects. Plant-based compounds such as flavonoids can absorb UVA and UVB rays and possess antioxidant, anticarcinogenic, and anti-inflammatory effects that contribute to photoprotection. Apart from flavonoids, other natural products such as certain vegetable oils, carotenoids, stilbenes, and ferulic acid also have UV-absorbing properties. Some vitamins might also be beneficial for skin protection due to their antioxidant activity. Therefore, the aim of this research was to gain insight into the potential of natural compounds to replace or reduce the amount of conventional UV filters, based on recent research. Full article

Cadmium (Cd) is a toxic heavy metal widely distributed in foodstuffs. In Mexico, few studies have evaluated Cd content in foods. This study aimed to determine Cd concentrations in foodstuffs that are highly consumed and bought in Mexico City to identify foods exceeding the Maximum Level (ML) and to assess the health risks of theoretical Cd intake from a diet following the Mexican Dietary Guidelines. A total of 143 foodstuffs were analyzed by atomic absorption spectrophotometry. Theoretical Cd intake was estimated in portions per week and compared with the Cd Tolerable Weekly Intake (TWI = 2.5 μg/kg per body weight). A total of 68.5% of the foodstuffs had detectable Cd concentrations. Higher concentrations were found in oyster mushrooms (0.575 mg/kg), romaine lettuce (0.335 mg/kg), and cocoa powder (0.289 mg/kg). Food groups with higher mean concentrations were vegetables (0.084 mg/kg) and snacks, sweets, and desserts (0.049 mg/kg). Ancho chili and romaine lettuce exceed the ML. The theoretical Cd intake estimation was 1.80, 2.05, and 3.82 μg/kg per body weight for adults, adolescents, and school-age children, respectively. This theoretical Cd intake represents a health risk only for school children exceeding the TWI by 53.2%. Our study confirms the presence and risk of Cd in Mexican foodstuffs and highlights the importance of monitoring programs. Full article

With the continuous progress of biomedical technology, biomaterial coatings play an important role in improving the performance of medical devices and promoting tissue repair and regeneration. The application of natural medicine to biological materials has become a hot topic due to its diverse biological activity, low toxicity, and wide range of sources. This article introduces the definition and classification of natural medicines, lists some common natural medicines, such as curcumin, allicin, chitosan, tea polyphenols, etc., and lists some biological activities of some common natural medicines, such as antibacterial, antioxidant, antitumor, and other properties. According to the different characteristics of natural medicines, physical adsorption, chemical grafting, layer-by-layer self-assembly, sol–gel and other methods are combined with biomaterials, which can be used for orthopedic implants, cardiovascular and cerebrovascular stents, wound dressings, drug delivery systems, etc., to exert their biological activity. For example, improving antibacterial properties, promoting tissue regeneration, and improving biocompatibility promote the development of medical health. Although the development of biomaterials has been greatly expanded, it still faces some major challenges, such as whether the combination between the coating and the substrate is firm, whether the drug load is released sustainably, whether the dynamic balance will be disrupted, and so on; a series of problems affects the application of natural drugs in biomaterial coatings. In view of these problems, this paper summarizes some suggestions by evaluating the literature, such as optimizing the binding method and release system; carrying out more clinical application research; carrying out multidisciplinary cooperation; broadening the application of natural medicine in biomaterial coatings; and developing safer, more effective and multi-functional natural medicine coatings through continuous research and innovation, so as to contribute to the development of the biomedical field. Full article

Finding new molecules to prevent the growth of antimicrobial resistance is a hot topic for scientists worldwide. It has been reported that some raw bioproducts containing Monascus polyketides have antimicrobial activities, but extensive studies on this effect have not been conducted. In this context, our studies aimed to evaluate the antimicrobial properties of six raw bioproducts containing three classes of microbial polyketides biosynthesized by three Monascus strains through solid-state biosynthesis. As a methodology, we performed in silico predictions using programs such as PyMOL v3.0.4 and employed ESI-MS techniques to provide evidence of the presence of the six studied compounds in our bioproducts. The results obtained in silico were validated through in vitro studies using the Kirby-Bauer diffusion method on bacteria and fungi. The test performed in silico showed that Monascorubramine has the highest affinity for both Gram-positive and Gram-negative bacteria, followed by yellow polyketides such as Ankaflavin and Monascin. The estimated pharmacokinetic parameters indicated high gastrointestinal absorption and the potential to cross the blood-brain barrier for all studied compounds. However, the compounds also inhibit most enzymes involved in drug metabolism, presenting some level of toxicity. The best in vitro results were obtained for S. aureus, with an extract containing yellow Monascus polyketides. Predictions made for E. coli were validated in vitro for P. aeruginosa, S. enterica, and S. marcescens, as well as for fungi. Significant antibacterial properties were observed during this study for C. albicans, S. aureus, and fungal dermatophytes for crude bioproducts containing Monascus polyketides. In conclusion, the antimicrobial properties of Monascus polyketides were validated both in silico and in vitro. However, due to their potential toxicity, these bioproducts would be safer to use as topical formulations. Full article

Environmental forces impacting public health include exposure to toxic substances, adverse childhood experiences (ACEs), diet, and exercise. Here, we examine the first two of these forces in some detail since they may be amenable to correction through cultural, medical, and practitioner intervention. At the same time, changing people’s dietary and exercise routines are likely more resistant to these interventions and are referred to only incidentally in this review. That is, societal efforts could prevent exposure to toxicants and ACEs—not necessarily requiring cooperation by the affected individuals—whereas changing diet and exercise practices requires an individual’s discipline. Toxic substances considered in this review include endocrine disruptors, arsenics, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the organic solvent, Trichloroethylene (TCE), and the Benzo[a]pyrene (B[a]P) produced from incomplete combustion of tobacco and other organic materials. Exposure to each of these toxic substances may have serious adverse health effects, especially in genetically more susceptible individuals. For example, children of mothers exposed to the endocrine disruptor, Atrazine, have significantly lower birth length, weight, and head circumference. Moreover, male offspring exhibit genital abnormalities, and all of these effects may be transgenerational. However, analyses of interactions among genes, the environment, and epigenetic modifications have already revealed distinctive individual risks of adverse reactions to toxic exposure. So, interventions through precision medicine might improve the health of those exposed individuals. Adults previously exposed to more than one ACE (e.g., child abuse and inter-parental violence) are more likely to develop anxiety, cancer, and diabetes. Detecting ACE exposures in children in the general population is fraught with difficulty. Thus, the risks of ACEs to our health remain even more insidious than exposures to toxicants. Nevertheless, higher provider compassion is associated with significantly better clinical outcomes for patients with these afflictions. For all these reasons, the first major aim of this review is to recount several of the major forces contributing to or impairing public health. Our second major aim is to examine mitigating influences on these forces, including social justice and provider compassion in the setting of precision medicine. Idealistically, these mitigators might eventually lead to the development of more cooperative and compassionate cultures and societies. Full article

Capecitabine (CAP) is one of the most commonly prescribed fluoropyrimidines in oncology, especially in the treatment of colon cancer. Cardiac toxicity is a severe and potentially lethal adverse drug reaction (ADR) against fluoropyrimidines. Cardiac ADRs, such as myocardial infarction (MI), heart failure (HF), arrhythmias, and a number of cardiomyopathies, are reported for these molecules. To have a better understanding of the risk–benefit ratio of colon cancer therapy, a pharmacovigilance study of real-world evidence of the cardiac toxicity of antineoplastic agents is required. Aim: This post-marketing research on CAP aims to assess the risk of cardiac toxicity. Five other antitumor drugs used in colorectal cancer, i.e., 5-fluorouracil (5-FU), irinotecan (IRI), oxaliplatin (OX), bevacizumab (BEV) and panitumumab (PAN), were also studied to create a relative profile of observed cardiotoxicity. Methods: A retrospective study based on reports submitted in the EudraVigilance (EV) database until 28 July 2024 was conducted. Using the aggregated data from EV, a descriptive analysis and disproportionality analysis of cardiac ADRs induced by fluoropyrimidines were performed. To evaluate the disproportionality of the signals, Reporting Odds Ratio (ROR) and 95% confidence interval (95% CI) were calculated by comparison with other drugs used in colorectal cancer: 5-FU, IRI, OX, BEV, and PAN. Results: “Cardiac disorders” represent 3.4% of the total reports for CAP. The value is comparable to 5-FU, but higher than for other drugs. t was observed that there are no significant differences in the occurrence of cardiac ADRs in patients exposed to CAP and 5-FU treatments, and in particular MI and HF. Compared to 5-FU, which could produce cardiac arrythmias with a higher probability than all other drugs, CAP has a higher probability of reporting this ADR only in comparison with IRI (ROR: 1.2971; 95% CI: 1.0196-1.6502). Conclusions: CAP induces adverse cardiovascular reactions, especially MI, HF, and cardiomyopathies. Arrhythmias have been shown to be side effects more frequent associated with 5-FU than with CAP. The results emphasize the need for a rigorous cardiovascular monitoring of patients following treatment with CAP or 5-FU and especially for those with pre-existing cardiac pathology. Full article

CAR-T therapy has revolutionized the field of oncology, offering a promising treatment option for cancer patients. However, the significant morbidity associated with therapy-related toxicity presents a major challenge to its widespread use. Despite extensive research into the underlying mechanisms of CAR-T therapy-related toxicity, there are still many unknowns. Furthermore, the lack of adequate in vitro models for assessing immunotoxicity and neurotoxicity further complicates the development of safer cellular therapies. Previously in our laboratory, we developed cancer-stroma spheres (CSS) composed of prostate adenocarcinoma PC3 cells and mesenchymal stem cells (MSC). Herein we present evidence that multicellular CSS could serve as a valuable in vitro model for toxicity studies related to CAR-T therapy. CSS containing CD19-overexpressing PC3M cells exhibited increased secretion of CAR-T cell toxicity-associated IL-8, MCP-1, and IP-10 in the presence of anti-CD19 CAR-T cells, compared to spheres derived from single cell types. Full article