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Frontiers in Toxicology 2024The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort,...
The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.
PubMed: 38933090
DOI: 10.3389/ftox.2024.1394361 -
Frontiers in Microbiology 2024The global rise in antimicrobial resistance (AMR) poses a significant public health threat, especially in healthcare settings, where controlling the spread of... (Review)
Review
The global rise in antimicrobial resistance (AMR) poses a significant public health threat, especially in healthcare settings, where controlling the spread of antimicrobial genes is crucial. While person-to-person transmission remains the primary route for healthcare-associated infections (HAIs), hospital surfaces serve as key reservoirs for antimicrobial-resistant microorganisms. Regular cleaning and disinfection of these surfaces are essential. Microbial-based products for sanitizing hospital surfaces have emerged as promising tools to combat HAIs and AMR. However, a review of 32 publications found inconsistencies and potential risks. A total of 15 publications included hospital-based trials, while the rest were either or assays, reviews, book chapters, or commentaries. In most of the hospital-based studies, specific strains of applied microorganisms were not identified, and the term "probiotic" was inaccurately used. These products mainly featured spores from and genera, which was mainly hypothesized to work through competitive exclusion. Most hospital-based studies have shown that the application of microbial-based products resulted in a significant reduction in pathogens on surfaces, thereby contributing to a decrease in the incidence of healthcare-associated infections (HAIs). Further research is however needed to understand the effectiveness, mechanisms of action, and safety of microbial-based sanitizing agents. Strain-level identification is crucial for safety assessments, yet many reviewed products lacked this information. Consequently, there is a need for rigorous safety evaluations within existing regulatory frameworks to ensure the efficacy and safety of microbial-based cleaning products in healthcare settings.
PubMed: 38933019
DOI: 10.3389/fmicb.2024.1412269 -
Frontiers in Cardiovascular Medicine 2024Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). Dysbiosis of gut microbiota has been implicated in age-related...
OBJECTIVE
Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). Dysbiosis of gut microbiota has been implicated in age-related diseases, but its role in AF development remains unclear. This study aimed to investigate the correlations between changes in the autonomic nervous system, short-chain fatty acids (SCFAs), and alterations in gut microbiota in aged rats with AF.
METHODS
Electrophysiological experiments were conducted to assess AF induction rates and heart rate variability in rats. 16S rRNA gene sequences extracted from fecal samples were used to assess the gut microbial composition. Gas and liquid chromatography-mass spectroscopy was used to identify SCFAs in fecal samples.
RESULTS
The study found that aged rats exhibited a higher incidence of AF and reduced heart rate variability compared to young rats. Omics research revealed disrupted gut microbiota in aged rats, specifically a decreased Firmicutes to Bacteroidetes ratio. Additionally, fecal SCFA levels were significantly lower in aged rats. Importantly, correlation analysis indicated a significant association between decreased SCFAs and declining heart rate variability in aged rats.
CONCLUSIONS
These findings suggest that SCFAs, as metabolites of gut microbiota, may play a regulatory role in autonomic nervous function and potentially influence the onset and progression of AF in aged rats. These results provide novel insights into the involvement of SCFAs and autonomic nervous system function in the pathogenesis of AF. These results provide novel insights into the involvement of SCFAs and autonomic nervous system function in the pathogenesis of AF.
PubMed: 38932988
DOI: 10.3389/fcvm.2024.1394929 -
Vaccines Jun 2024spp. are responsible for bacillary dysentery or shigellosis transmitted via the fecal-oral route, causing significant morbidity and mortality, especially among...
spp. are responsible for bacillary dysentery or shigellosis transmitted via the fecal-oral route, causing significant morbidity and mortality, especially among vulnerable populations. There are currently no licensed vaccines. spp. use a type III secretion system (T3SS) to invade host cells. We have shown that L-DBF, a recombinant fusion of the T3SS needle tip (IpaD) and translocator (IpaB) proteins with the LTA1 subunit of enterotoxigenic labile toxin, is broadly protective against spp. challenge in a mouse lethal pulmonary model. Here, we assessed the effect of LDBF, formulated with a unique TLR4 agonist called BECC470 in an oil-in-water emulsion (ME), on the murine immune response in a high-risk population (young and elderly) in response to challenge. Dual RNA Sequencing captured the transcriptome during infection in vaccinated and unvaccinated mice. Both age groups were protected by the L-DBF formulation, while younger vaccinated mice exhibited more adaptive immune response gene patterns. This preliminary study provides a step toward identifying the gene expression patterns and regulatory pathways responsible for a protective immune response against . Furthermore, this study provides a measure of the challenges that need to be addressed when immunizing an aging population.
PubMed: 38932347
DOI: 10.3390/vaccines12060618 -
Pharmaceuticals (Basel, Switzerland) Jun 2024The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical... (Review)
Review
The enduring relationship between humanity and the cannabis plant has witnessed significant transformations, particularly with the widespread legalization of medical cannabis. This has led to the recognition of diverse pharmacological formulations of medical cannabis, containing 545 identified natural compounds, including 144 phytocannabinoids like Δ9-THC and CBD. Cannabinoids exert distinct regulatory effects on physiological processes, prompting their investigation in neurodegenerative diseases. Recent research highlights their potential in modulating protein aggregation and mitochondrial dysfunction, crucial factors in conditions such as Alzheimer's Disease, multiple sclerosis, or Parkinson's disease. The discussion emphasizes the importance of maintaining homeodynamics in neurodegenerative disorders and explores innovative therapeutic approaches such as nanoparticles and RNA aptamers. Moreover, cannabinoids, particularly CBD, demonstrate anti-inflammatory effects through the modulation of microglial activity, offering multifaceted neuroprotection including mitigating aggregation. Additionally, the potential integration of cannabinoids with vitamin B12 presents a holistic framework for addressing neurodegeneration, considering their roles in homeodynamics and nervous system functioning including the hippocampal neurogenesis. The potential synergistic therapeutic benefits of combining CBD with vitamin B12 underscore a promising avenue for advancing treatment strategies in neurodegenerative diseases. However, further research is imperative to fully elucidate their effects and potential applications, emphasizing the dynamic nature of this field and its potential to reshape neurodegenerative disease treatment paradigms.
PubMed: 38931480
DOI: 10.3390/ph17060813 -
Pharmaceuticals (Basel, Switzerland) May 2024Despite the vast global botanical diversity, the pharmaceutical development of herbal medicinal products (HMPs) remains underexploited. Of over 370,000 described plant...
Despite the vast global botanical diversity, the pharmaceutical development of herbal medicinal products (HMPs) remains underexploited. Of over 370,000 described plant species, only a few hundred are utilized in HMPs. Most of these have originated from traditional use, and only a minority come from megadiverse countries. Exploiting the pharmacological synergies of the hundreds of compounds found in poorly studied plant species may unlock new therapeutic possibilities, enhance megadiverse countries' scientific and socio-economic development, and help conserve biodiversity. However, extensive constraints in the development process of HMPs pose significant barriers to transforming this unsatisfactory socio-economic landscape. This paper proposes a roadmap to overcome these challenges, based on the technology readiness levels (TRLs) introduced by NASA to assess the maturity of technologies. It aims to assist research entities, manufacturers, and funding agencies from megadiverse countries in the discovery, development, and global market authorization of innovative HMPs that comply with regulatory standards from ANVISA, EMA, and FDA, as well as WHO and ICH guidelines.
PubMed: 38931370
DOI: 10.3390/ph17060703 -
Plants (Basel, Switzerland) Jun 2024is an important component of China's economic development and forest ecosystems. The growth of seedlings experienced a slow growth phase, which led to a long seedling...
is an important component of China's economic development and forest ecosystems. The growth of seedlings experienced a slow growth phase, which led to a long seedling cultivation period. However, asexual reproduction can ensure the stable inheritance of the superior traits of the mother tree and also shorten the breeding cycle. The quantity and quality of branching significantly impact the cutting reproduction of , and a shaded environment affects lateral branching growth, development, and photosynthesis. Nonetheless, the physiological characteristics and the level of the transcriptome that underlie the growth of lateral branches of under shade conditions are still unclear. In our experiment, we subjected annual seedlings to varying shade intensities (0%, 25%, 50%, 75%) and studied the effects of shading on growth, physiological and biochemical changes, and gene expression in branching. Results from this study show that shading reduces biomass production by inhibiting the branching ability of seedlings. Due to the regulatory and protective roles of osmotically active substances against environmental stress, the contents of soluble sugars, soluble proteins, photosynthetic pigments, and enzyme activities exhibit varying responses to different shading treatments. Under shading treatment, the contents of phytohormones were altered. Additionally, genes associated with phytohormone signaling and photosynthetic pathways exhibited differential expression. This study established a theoretical foundation for shading regulation of lateral branch growth and provides scientific evidence for the management of cutting orchards.
PubMed: 38931020
DOI: 10.3390/plants13121588 -
Journal of Clinical Medicine Jun 2024Nanoengineering has emerged as a progressive method in cancer treatment, offering precise and targeted delivery of therapeutic agents while concurrently reducing overall...
Nanoengineering has emerged as a progressive method in cancer treatment, offering precise and targeted delivery of therapeutic agents while concurrently reducing overall toxicity. This scholarly article delves into the innovative strategies and advancements in nanoengineering that bridge the gap between clinical practice and research in the field of cancer treatment. Various nanoengineered platforms such as nanoparticles, liposomes, and dendrimers are scrutinized for their capacity to encapsulate drugs, augment drug efficacy, and enhance pharmacokinetics. Moreover, the article investigates research breakthroughs that drive the progression and enhancement of nanoengineered remedies, encompassing the identification of biomarkers, establishment of preclinical models, and advancement of biomaterials, all of which are imperative for translating laboratory findings into practical medical interventions. Furthermore, the integration of nanotechnology with imaging modalities, which amplify cancer detection, treatment monitoring, and response assessment, is thoroughly examined. Finally, the obstacles and prospective directions in nanoengineering, including regulatory challenges and issues related to scalability, are examined. This underscores the significance of fostering collaboration among various entities in order to efficiently translate nanoengineered interventions into enhanced cancer therapies and patient management.
PubMed: 38929995
DOI: 10.3390/jcm13123466 -
Journal of Personalized Medicine Jun 2024Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD)...
Development Perspectives for Curative Technologies in Primary Demyelinating Disorders of the Central Nervous System with Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) at the Forefront.
Primary demyelinating disorders of the central nervous system (CNS) include multiple sclerosis and the orphan conditions neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD). Curative technologies under development aim to selectively block autoimmune reactions against specific autoantigens while preserving the responsiveness of the immune system to other antigens. Our analysis focused on target patient selection for such developments, carefully considering the relevant clinical, regulatory, and market-related aspects. We found that the selection of patients with orphan conditions as target populations offers several advantages. Treatments for orphan conditions are associated with limited production capacity, qualify for regulatory incentives, and may require significantly shorter and lower-scale clinical programs. Furthermore, they may meet a higher acceptable cost-effectiveness threshold in order to compensate for the low numbers of patients to be treated. Finally, curative technologies targeting orphan indications could enter less competitive markets with lower risk of generic price erosion and would benefit from additional market protection measures available only for orphan products. These advantages position orphan conditions and subgroups as the most attractive target indications among primary demyelinating disorders of the CNS. The authors believe that after successful proof-of-principle demonstrations in orphan conditions, broader autoimmune patient populations may also benefit from the success of these pioneering developments.
PubMed: 38929820
DOI: 10.3390/jpm14060599 -
International Journal of Molecular... Jun 2024Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the... (Review)
Review
Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field.
Topics: Humans; Vaccines, Virus-Like Particle; Nanoparticles; Animals; Virion; Drug Delivery Systems
PubMed: 38928403
DOI: 10.3390/ijms25126699