Neurotoxicant effects of bisphenol A, nonylphenol, and tert­butyl phenol in the Nile tilapia (Oreochromis niloticus).

Worldwide production of alkyl phenols and ethoxylated alkyl phenols is high due to their broad industrial uses. It has been widely documented that they are endocrine disruptors, and it has been suggested that they could exert neurotoxic effects. However, a lack of information about the neurotoxic effects of APs and APEs prevails. In this study, the bisphenol A (BPA), 4-nonylphenol (NP), and 3­tert-butylphenol (tertBP) effects on brain and spinal cord of Nile tilapia exposed to environmental concentrations were evaluated by assessing acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and carboxylesterases (CES) activities, and γ-aminobutyric acid (GABA) levels and their effects were evaluated by molecular docking. BPA and NP, tertBP behave as agonists and antagonists of AChE, BuChE, CES, and GABA, with notable differences among organs. However, none of these compounds or their metabolites interact with the enzymes' catalytic triad, suggesting an indirect alteration of enzymatic activities. While inhibiting these enzymes stand out hydrophobic interactions with the peripheral anion site, contacts with the inner face of the active site and blocking the mouth of the gorge of the active site, and steric hindrance in the enzyme pocket of glutamate decarboxylase (GAD). In contrast, inductions probably are by homotropic pseudo-cooperative phenomenon, where APEs behave as anchors favoring the active site to remain open and interactions that confer a conservative stabilization of the regulatory domain. Although the results of this study are complex, with notable differences between organs and toxicants, they are some of the first evidence of the neurotoxicity of alkylphenols and their ethoxylated derivatives.

Serious Adverse Events of Inclisiran in Patients With Hypercholesterolemia, a Meta-Analysis of ORION Trials.

BACKGROUND: Several studies have been conducted over the years to find an effective and safe therapeutic agent to treat hypercholesterolemia. Inclisiran is a novel drug being studied for its efficacy and safety in reducing low-density lipoprotein cholesterol levels in patients to reduce the risk of cardiovascular diseases. No previous study was done to review the trials for the serious adverse events of this drug. The primary objective of this research is to investigate the incidence of serious adverse events of this drug. DESIGN: A systematic review and meta-analysis of clinical trials is performed. METHODS: A systematic search of PubMed, Embase, and ClinicalTrials.gov, from their inception till July 3, 2023, was performed for ORION trials, studying the efficacy and safety of inclisiran. The random-effects model was used in the meta-analysis to provide a pooled proportion of serious adverse events. The risk of bias in each study was assessed by the Cochrane Risk of Bias Tool. RESULTS: From 319 studies searched from the databases, only 8 relevant articles remained after a detailed evaluation. These studies, having a total of 4981 patients, were involved in the analysis, with a pooled estimate showing a nonsignificant incidence of serious adverse events. Each adverse event was studied individually, and product issues and endocrine disorders had the highest odds ratio among them. All included studies were classified as moderate quality. CONCLUSION: Following systematic review and meta-analysis, we found no significant differences in any serious adverse events following the administration of inclisiran. However, larger ongoing trials will provide additional data to evaluate the safety profile of this agent.

Tumor-Infiltrating iNKT Cells Activated through c-Kit/Sca-1 Are Induced by Pentoxifylline, Norcantharidin, and Their Mixtures for Killing Murine Melanoma Cells.

The involvement of NK and other cytotoxic cells is considered the first defense line against cancer. However, a significant lack of information prevails on the possible roles played by factors considered characteristic of primitive cells, such as c-kit and Sca-1, in activating these cells, particularly in melanoma models subjected to treatments with substances under investigation, such as the case of norcantharidin. In this study, B16F1 murine melanoma cells were used to induce tumors in DBA/2 mice, estimating the proportions of NK and iNKT cells; the presence of activation (CD107a+) and primitive/activation (c-kit+/Lya6A+) markers and some tumor parameters, such as the presence of mitotic bodies, nuclear factor area, NK and iNKT cell infiltration in the tumor, infiltrated tumor area, and infiltrating lymphocyte count at 10x and 40x in specimens treated with pentoxifylline, norcantharidin, and the combination of both drugs. Possible correlations were estimated with Pearson's correlation analysis. It should be noted that, despite having demonstrated multiple correlations, immaturity/activation markers were related to these cells' activation. At the tumor site, iNKT cells are the ones that exert the cytotoxic potential on tumor cells, but they are confined to specific sites in the tumor. Due to the higher number of interactions of natural killer cells with tumor cells, it is concluded that the most effective treatment was PTX at 60 mg/kg + NCTD at 0.75 mg/kg.

Effectiveness of radiotherapy and targeted radionuclide therapy for melanoma in preclinical mouse models: A combination treatments overview.

Cutaneous melanoma is an aggressive and highly metastatic skin cancer. In recent years, immunotherapy and targeted small-molecule inhibitors have improved the overall survival of patients. Unfortunately, most patients in advanced stages of disease exhibit either intrinsically resistant or rapidly acquire resistance to these approved treatments. However, combination treatments have emerged to overcome resistance, and novel treatments based on radiotherapy (RT) and targeted radionuclide therapy (TRT) have been developed to treat melanoma in the preclinical mouse model, raising the question of whether synergy in combination therapies may motivate and increase their use as primary treatments for melanoma. To help clarify this question, we reviewed the studies in preclinical mouse models where they evaluated RT and TRT in combination with other approved and unapproved therapies from 2016 onwards, focusing on the type of melanoma model used (primary tumor and or metastatic model). PubMed® was the database in which the search was performed using mesh search algorithms resulting in 41 studies that comply with the inclusion rules of screening. Studies reviewed showed that synergy with RT or TRT had strong antitumor effects, such as tumor growth inhibition and fewer metastases, also exhibiting systemic protection. In addition, most studies were carried out on antitumor response for the implanted primary tumor, demonstrating that more studies are needed to evaluate these combined treatments in metastatic models on long-term protocols.

Combinational photodynamic and photothermal - based therapies for melanoma in mouse models.

BACKGROUND: Melanoma is a highly metastatic skin cancer with limited response to current therapies in advanced patients. To overcome resistance, novel treatments based on photodynamic and photothermal therapies (PDT and PTT, respectively) have been developed to treat melanoma in preclinical murine models. Despite success inhibiting implanted tumors' growth, there has been limited evaluation of their long-term effectiveness in preventing metastasis, recurrence, or improving survival rates. METHODS: Combined and multidrug therapies based on PDT and/or PTT to treat cutaneous malignant melanoma in the preclinical mouse model were reviewed from 2016 onwards. PubMed® was the database in which the search was performed using mesh search algorithms resulting in fifty-one studies that comply with strict inclusion rules of screening. RESULTS: B16 melanoma-bearing C57BLACK6 mice model was the most used to evaluate immunotherapies, chemotherapies, and targeted therapies in combination with PDT and/or PTT. Combined therapies demonstrated a synergistic effect, resulting in intense antitumor activity. The most extensively studied protocol for developing metastatic models involved the intravenous administration of malignant cells, with some combined therapies being tested. Furthermore, the review presents the composition of the nanostructures utilized for delivering the drugs and light-responsive agents and the treatment plans for each combined approach. CONCLUSIONS: The identified mechanisms to simulate metastatic melanoma models and the therapeutic combinations may aid in evaluating the systemic protection of combined PDT and PTT-based therapies, particularly in conducting short-term preclinical experiments. Such simulations could have relevance to clinical studies.