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Veterinary Medicine and Science Jul 2024Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of...
BACKGROUND
Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties.
OBJECTIVES
The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C.
METHODS
The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis.
RESULTS
The elimination half-life (t) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent.
CONCLUSIONS
While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.
Topics: Animals; Oncorhynchus mykiss; ortho-Aminobenzoates; Biological Availability; Anti-Inflammatory Agents, Non-Steroidal; Administration, Oral; Blood Proteins; Injections, Intramuscular; Protein Binding; Injections, Intravenous; Half-Life
PubMed: 38952278
DOI: 10.1002/vms3.1533 -
Lifestyle Genomics Jul 2024This study aims to investigate if a mixture of functional lipids (FL), containing conjugated linoleic acid (CLA), tocopherols (TP) and phytosterols (PS) prevents some...
INTRODUCTION
This study aims to investigate if a mixture of functional lipids (FL), containing conjugated linoleic acid (CLA), tocopherols (TP) and phytosterols (PS) prevents some lipid alterations induced by high-fat (HF) diets, without adverse effects.
METHODS
Male CF1 mice (n=6/group) were fed (4 weeks) with: control (C), HF or HF+FL diets.
RESULTS
FL prevented the overweight induced by the HF diet, and reduced the adipose tissues (AT) weight, associated with lower energy efficiency. After the intervention period, the serum triacylglycerol (TAG) levels, in both HF diets underwent a decrease associated with an enhanced LPL activity (mainly in muscle). The beneficial effect of the FL mixture on body weight gain and AT weight, might be attributed to the decreased lipogenesis, denoted by the lower mRNA levels of SREBP1-c and ACC in AT, as well as, by an exacerbated lipid catabolism, reflected by increased mRNA levels of PPARα, ATGL, HSL and UCP2 in adipose tissue. Liver TAG levels were reduced in the HF+FL group due to an elevated lipid oxidation associated with a higher CPT-1 activity and mRNA levels of PPARα and CPT-1a. Moreover, genes linked to fatty acid biosynthesis (SREBP1-c and ACC) showed decreased mRNA levels in both HF diets, this finding being more pronounced in the HF+FL group.
CONCLUSION
The administration of a FL mixture (CLA+TP+PS) prevented some lipid alterations induced by a HF diet, avoiding frequent deleterious effects of CLA in mice through the modulation of gene expression related to the regulation of lipid metabolism.
PubMed: 38952113
DOI: 10.1159/000539077 -
Journal of Biosciences 2024Owing to the lack of effective vaccines, current control measures and eradication strategies for the African swine fever virus (ASFV) rely on early detection and... (Comparative Study)
Comparative Study
Owing to the lack of effective vaccines, current control measures and eradication strategies for the African swine fever virus (ASFV) rely on early detection and stringent stamping-out procedures. In the present study, we developed two independent isothermal amplification assays, namely, loop-mediated isothermal amplification (LAMP) and polymerase spiral reaction (PSR), for quick visualization of the ASFV genome in clinical samples. Additionally, a quantitative real-time PCR (qRT-PCR)-based hydrolysis probe assay was developed for comparative assessment of sensitivity with the developed isothermal assays. The analytical sensitivity of the LAMP, PSR, and qRT-PCR was found to be 2.64 ×10 copies/µL, 2.64 ×10 copies/µL, and 2.64 ×10 copies/µL, respectively. A total of 165 clinical samples was tested using the developed visual assays. The relative accuracy, relative specificity, and relative diagnostic sensitivity for LAMP vs PSR were found to be 95.37% vs 102.48%, 97.46% vs 101.36%, and 73.33% vs 113.33%, respectively.
Topics: African Swine Fever Virus; Animals; Nucleic Acid Amplification Techniques; Swine; African Swine Fever; Sensitivity and Specificity; Real-Time Polymerase Chain Reaction; Molecular Diagnostic Techniques; Genome, Viral
PubMed: 38952078
DOI: No ID Found -
International Journal of Stem Cells Jul 2024Histone H2B monoubiquitination (H2Bub1) is a dynamic posttranslational modification which are linked to DNA damage and plays a key role in a wide variety of regulatory...
Histone H2B monoubiquitination (H2Bub1) is a dynamic posttranslational modification which are linked to DNA damage and plays a key role in a wide variety of regulatory transcriptional programs. Cancer cells exhibit a variety of epigenetic changes, particularly any aberrant H2Bub1 has frequently been associated with the development of tumors. Nevertheless, our understanding of the mechanisms governing the histone H2B deubiquitination and their associated functions during stem cell differentiation remain only partially understood. In this study, we wished to investigate the role of deubiquitinating enzymes (DUBs) on H2Bub1 regulation during stem cell differentiation. In a search for potential DUBs for H2B monoubiquitination, we identified Usp7, a ubiquitin-specific protease that acts as a negative regulator of H2B ubiquitination during the neuronal differentiation of mouse embryonic carcinoma cells. Loss of function of the gene by a CRISPR/Cas9 system during retinoic acid-mediated cell differentiation contributes to the increase in H2Bub1. Furthermore, knockout of the gene particularly elevated the expression of neuronal differentiation related genes including astryocyte-specific markers and oligodendrocyte-specific markers. In particular, glial lineage cell-specific transcription factors including oligodendrocyte transcription factor 2, glial fibrillary acidic protein, and SRY-box transcription factor 10 was significantly upregulated during neuronal differentiation. Thus, our findings suggest a novel role of Usp7 in gliogenesis in mouse embryonic carcinoma cells.
PubMed: 38952059
DOI: 10.15283/ijsc23202 -
Animal Models and Experimental Medicine Jul 2024Artesunate (ASA) acts as an •O₂ source through the breakdown of endoperoxide bridges catalyzed by Fe, yet its efficacy in ASA-based nanodrugs is limited by poor...
BACKGROUND
Artesunate (ASA) acts as an •O₂ source through the breakdown of endoperoxide bridges catalyzed by Fe, yet its efficacy in ASA-based nanodrugs is limited by poor intracellular delivery.
METHODS
ASA-hyaluronic acid (HA) conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first, and then self-targeting nanomicelles (NM) were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments.
RESULTS
These ASA-HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells. Subsequently, endogenous Fe from the tumor catalyzes the released ASA to produce highly toxic •O₂ radicals to kill tumor cells, although sustained tumor growth inhibition can be achieved via in vivo experiments.
CONCLUSIONS
Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments, leveraging clinically approved drugs to expedite drug development and clinical research in oncology.
PubMed: 38952042
DOI: 10.1002/ame2.12468 -
Journal of Clinical Neurology (Seoul,... Jul 2024Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on...
BACKGROUND AND PURPOSE
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on MADD that describes the phenotypic and genetic features of a Malaysian cohort.
METHODS
Among the >2,500 patients in a local muscle biopsy database, patients with LSM were identified and their genomic DNA were extracted from muscle samples and peripheral blood. All 13 exons of the electron-transfer flavoprotein dehydrogenase gene () were subsequently sequenced. Fifty controls were included to determine the prevalence of identified mutations in the normal population.
RESULTS
Fourteen (82%) of the 17 LSM patients had MADD with mutations. Twelve (86%) were Chinese and two were Malay sisters. Other unrelated patients reported that they had no relevant family history. Nine (64%) were females. The median age at onset was 18.5 years (interquartile range=16-37 years). All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. Three patients experienced a metabolic crisis at their presentation. Sanger sequencing of revealed nine different variants/mutations, one of which was novel: c.998A>G (p.Y333C) in exon 9. Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China. All of the patients responded well to riboflavin therapy.
CONCLUSIONS
Most of our Malaysian cohort with LSM had late-onset, riboflavin-responsive MADD with mutations, and they demonstrated phenotypic and genetic features similar to those of cases reported in southern China. Furthermore, we report a novel mutation and possibly the first ever MADD patients of Malay descent.
PubMed: 38951975
DOI: 10.3988/jcn.2023.0265 -
Orthopaedic Surgery Jul 2024Total hip arthroplasty (THA) remains the primary treatment option for femoral neck fractures in elderly patients. This study aims to explore the risk factors associated...
Development and Validation of a Machine Learning Algorithm to Predict the Risk of Blood Transfusion after Total Hip Replacement in Patients with Femoral Neck Fractures: A Multicenter Retrospective Cohort Study.
OBJECTIVE
Total hip arthroplasty (THA) remains the primary treatment option for femoral neck fractures in elderly patients. This study aims to explore the risk factors associated with allogeneic blood transfusion after surgery and to develop a dynamic prediction model to predict post-operative blood transfusion requirements. This will provide more accurate guidance for perioperative humoral management and rational allocation of medical resources.
METHODS
We retrospectively analyzed data from 829 patients who underwent total hip arthroplasty for femoral neck fractures at three third-class hospitals between January 2017 and August 2023. Patient data from one hospital were used for model development, whereas data from the other two hospitals were used for external validation. Logistic regression analysis was used to screen the characteristic subsets related to blood transfusion. Various machine learning algorithms, including logistic regression, SVA (support vector machine), K-NN (k-nearest neighbors), MLP (multilayer perceptron), naive Bayes, decision tree, random forest, and gradient boosting, were used to process the data and construct prediction models. A 10-fold cross-validation algorithm facilitated the comparison of the predictive performance of the models, resulting in the selection of the best-performing model for the development of an open-source computing program.
RESULTS
BMI (body mass index), surgical duration, IBL (intraoperative blood loss), anticoagulant history, utilization rate of tranexamic acid, Pre-Hb, and Pre-ALB were included in the model as well as independent risk factors. The average area under curve (AUC) values for each model were as follows: logistic regression (0.98); SVA (0.91); k-NN (0.87) MLP, (0.96); naive Bayes (0.97); decision tree (0.87); random forest (0.96); and gradient boosting (0.97). A web calculator based on the best model is available at: (https://nomo99.shinyapps.io/dynnomapp/).
CONCLUSION
Utilizing a computer algorithm, a prediction model with a high discrimination accuracy (AUC > 0.5) was developed. The logistic regression model demonstrated superior differentiation and reliability, thereby successfully passing external validation. The model's strong generalizability and applicability have significant implications for clinicians, aiding in the identification of patients at high risk for postoperative blood transfusion.
PubMed: 38951965
DOI: 10.1111/os.14160 -
Environmental Health : a Global Access... Jul 2024Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the...
BACKGROUND
Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships.
METHODS
We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation.
RESULTS
Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (β = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (β = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (β = 23 g; 95% CI: -25, 71) compared to those with higher educational status (β = -9 g; 95% CI: -24, 6).
CONCLUSIONS
Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.
Topics: Humans; Female; Pregnancy; Hydrocarbons, Chlorinated; Birth Weight; Maternal Exposure; Adult; Environmental Pollutants; Canada; Infant, Newborn; Young Adult; Metals; Socioeconomic Factors; Cohort Studies; Male
PubMed: 38951908
DOI: 10.1186/s12940-024-01095-x -
Journal of Translational Medicine Jul 2024Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil...
BACKGROUND
Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil.
METHODS
We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo.
RESULTS
Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo.
CONCLUSIONS
This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.
Topics: Triple Negative Breast Neoplasms; Aptamers, Nucleotide; Humans; Paclitaxel; Nucleolin; Cell Line, Tumor; Animals; Female; Fluorouracil; Drug Liberation; RNA-Binding Proteins; Delayed-Action Preparations; Phosphoproteins; Oligodeoxyribonucleotides; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Xenograft Model Antitumor Assays; Cell Proliferation; Oxidation-Reduction; Mice, Inbred BALB C
PubMed: 38951906
DOI: 10.1186/s12967-024-05429-8 -
Cancer & Metabolism Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.
METHODS
Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.
RESULTS
Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.
CONCLUSIONS
Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.
PubMed: 38951899
DOI: 10.1186/s40170-024-00346-2