European Mistletoe (Viscum album) Extract Is Cytotoxic to Canine High-Grade Astrocytoma Cells In Vitro and Has Additive Effects with Mebendazole

Malignant gliomas are associated with extremely poor clinical outcomes in both humans and dogs, and novel therapies are needed. Glioma-bearing canine patients may serve as promising preclinical models for human therapies, including complementary medicine. The objective of this study was to evaluate the effects of mistletoe extract (Viscum album) alone and in combination with mebendazole in an in vitro model of canine high-grade astrocytoma using the cell line SDT-3G. SDT-3G cells were exposed to a range of concentrations of mistletoe extract alone to obtain an IC50. In separate experiments, cells were exposed to mebendazole at a previously determined IC50 (0.03 µM) alone or in conjunction with varying concentrations of mistletoe extract to determine the additive effects. The IC50 for mistletoe alone was 5.644 ± 0.09 SD μg/mL. The addition of mistletoe at 5 μg/mL to mebendazole at 0.03 µM led to increased cell death compared to what would be expected for each drug separately. The cytotoxicity of mistletoe in vitro and its additive effect with mebendazole support future expanded in vitro and in vivo studies in dogs and supply early evidence that this may be a useful adjunct therapeutic agent for use in glioma-bearing dogs. To the authors’ knowledge, this is the first published report of Viscum album extract in canine glioma.

Childhood Disadvantage and Adult Functional Status: Do Early-Life Exposures Jeopardize Healthy Aging?

Objectives To examine whether childhood disadvantage is associated with later-life functional status and identify mediating factors. Methods Unique and additive effects of five childhood domains on functional status were assessed at baseline (2006) and over time (2006–2016) in a sample of 13,894 adults from the Health and Retirement Study (>50 years). Adult health behaviors and socioeconomic status (SES) were tested as mediators. Results Respondents exposed to multiple childhood disadvantages (OR = .694) as well as low childhood SES (OR = .615), chronic diseases (OR = .694), impairments (OR = .599), and risky adolescent behaviors (OR = .608) were less likely to be free of functional disability by baseline. Over time, these unique and additive effects of childhood disadvantage increased the hazard odds of eventually developing functional disability (e.g., additive effect: hOR = 1.261). Adult health behaviors and SES mediated some of these effects. Discussion Given the enduring effects of childhood disadvantage, policies to promote healthy aging should reduce exposure to childhood disadvantage.

Genomic Analysis of Visceral Fat Accumulation in Holstein Cows

Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes, pathways, and molecular processes implicated in visceral fat deposition in dairy cows. Data from 172 genotyped Holstein cows classified at slaughterhouse as having low (n = 77; omental fold <5 mm in thickness and minimum fat deposition in omentum) or high (n = 95; omental fold ≥20 mm in thickness and marked fat deposition in omentum) omental fat were analyzed. The identification of regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as SMAD7, ANKRD55, and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects. These regions harbor genes MRAP, MIS18A, PRNP and TSHZ1, that are directly implicated in adipocyte differentiation, lipid metabolism, and insulin sensitivity. The gene-set analysis revealed functional terms related to cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, and membrane permeability, among other functions. We further evaluated the genetic link between visceral fat and two metabolic disorders, ketosis, and displaced abomasum. For this, we analyzed 28k records of incidence of metabolic disorders from 14k cows across lactations using a single-step genomic BLUP approach. Notably, the region on BTA20 significantly associated with visceral fat deposition was also associated with the incidence of displaced abomasum. Overall, our findings suggest that visceral fat deposition in dairy cows is controlled by both additive and non-additive effects. We detected at least one region with marked pleiotropic effects affecting both visceral fat accumulation and displaced abomasum.

Liraglutide Activates Type 2 Deiodinase and Enhances β3-Adrenergic-Induced Thermogenesis in Mouse Adipose Tissue

AimsLiraglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist used as an anti-hyperglycemic agent in type 2 diabetes treatment and recently approved for obesity management. Weight loss is attributed to appetite suppression, but therapy may also increase energy expenditure. To further investigate the effect of GLP-1 signaling in thermogenic fat, we assessed adipose tissue oxygen consumption and type 2 deiodinase (D2) activity in mice treated with liraglutide, both basally and after β3-adrenergic treatment.MethodsMale C57BL/6J mice were randomly assigned to receive liraglutide (400 μg/kg, n=12) or vehicle (n=12). After 16 days, mice in each group were co-treated with the selective β3-adrenergic agonist CL316,243 (1 mg/kg, n=6) or vehicle (n=6) for 5 days. Adipose tissue depots were assessed for gene and protein expression, oxygen consumption, and D2 activity.ResultsLiraglutide increased interscapular brown adipose tissue (iBAT) oxygen consumption and enhanced β3-adrenergic-induced oxygen consumption in iBAT and inguinal white adipose tissue (ingWAT). These effects were accompanied by upregulation of UCP-1 protein levels in iBAT and ingWAT. Notably, liraglutide increased D2 activity without significantly upregulating its mRNA levels in iBAT and exhibited additive effects to β3-adrenergic stimulation in inducing D2 activity in ingWAT.ConclusionsLiraglutide exhibits additive effects to those of β3-adrenergic stimulation in thermogenic fat and increases D2 activity in BAT, implying that it may activate this adipose tissue depot by increasing intracellular thyroid activation, adding to the currently known mechanisms of GLP-1A-induced weight loss.

Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A

Although some therapeutic progress has been achieved in developing small molecules that correct F508del-CFTR defects, the mechanism of action (MoA) of these compounds remain poorly elucidated. Here, we investigated the effects and MoA of MCG1516A, a newly developed F508del-CFTR corrector. MCG1516A effects on wild-type (WT) and F508del-CFTR were assessed by immunofluorescence microscopy, and biochemical and functional assays both in cell lines and in intestinal organoids. To shed light on the MoA of MCG1516A, we evaluated its additivity to the FDA-approved corrector VX-661, low temperature, genetic revertants of F508del-CFTR (G550E, R1070W, and 4RK), and the traffic-null variant DD/AA. Finally, we explored the ability of MCG1516A to rescue trafficking and function of other CF-causing mutations. We found that MCG1516A rescues F508del-CFTR with additive effects to VX-661. A similar behavior was observed for WT-CFTR. Under low temperature incubation, F508del-CFTR demonstrated an additivity in processing and function with VX-661, but not with MCG1516A. In contrast, both compounds promoted additional effects to low temperature to WT-CFTR. MCG1516A demonstrated additivity to genetic revertant R1070W, while VX-661 was additive to G550E and 4RK. Nevertheless, none of these compounds rescued DD/AA trafficking. Both MCG1516A and VX-661 rescued CFTR processing of L206W- and R334W-CFTR with greater effects when these compounds were combined. In summary, the absence of additivity of MCG1516A to genetic revertant G550E suggests a putative binding site for this compound on NBD1:NBD2 interface. Therefore, a combination of MCG1516A with compounds able to rescue DD/AA traffic, or mimicking the actions of revertant R1070W (e.g., VX-661), could enhance correction of F508del-CFTR defects.

Genomic Analysis of Purebred and Crossbred Angus Cows Quantifies Heterozygosity, Breed, and Additive Effects on Components of Reproduction

Multiple studies have quantified the production differences of Hereford Angus crossbreds compared to purebred Angus for a range of traits including growth, carcass, and reproductive traits. This study aims to quantify breed and heterosis effects on maternal performance using genomics. Thirty Hereford and thirty Angus sires were mated to 1100 Angus heifers and cows in a large commercial herd run on pasture at Musselroe Bay, Tasmania, Australia. Approximately 1650 calves were born. Heifers were weaned, scanned for attainment of puberty prior to joining at approximately 15 months of age, joined, and then recorded for status of pregnancy, calving, lactating, 2nd pregnancy, and weaning of second calf. Heterozygosity effects were significant for heifer pre-joining weight and height as well as proportion pubertal. Breed differences were significant for the same traits plus pregnancy rate at second joining and proportion rearing two calves. Genetic parameters were reported for 13 traits. On average, higher genetic merit (Estimated Breeding Value, EBV percentile) Hereford bulls were used than Angus for growth and puberty, but they were similar for fat and reproduction. Days to calving BREEDPLAN EBVs of the sires were related to puberty and reproduction. Scrotal size BREEDPLAN EBVs of the sires were related to attainment of puberty genomic EBVs calculated. In summary, breed differences in growth and puberty were due to heterosis, but there was an advantage of Hereford genes for reproductive performance. Ongoing emphasis on selection for reduced days to calving and estimation of multi-breed EBVs is important.

A Review on Contaminants of Emerging Concern in the Environment: A Focus on Active Chemicals in Sub-Saharan Africa

Active chemicals are among the contaminants of emerging concern that are rarely covered in regulatory documents in sub-Saharan Africa. These substances are neither in the list of routinely monitored substances nor in the guidelines for routine environmental monitoring activities. This has been of concern to public health officials, toxicologists, communities, and governments, hence the need for risk assessment and regulation of these substances. In this review article, the presence of active chemicals in the sub-Saharan African environment was investigated. The results indicate the availability of few studies in some countries, while in other countries no reports of active chemicals were found, hence the need for further research targeting such countries. It was further observed that mixtures of active chemicals from different therapeutic categories—such as antibiotics and analgesics—were reported. The natural environment is increasingly at risk due to the presence of these substances, their metabolites, and their transformation byproducts. These substances are characterized by persistence as a result of their non-biodegradable nature; hence, they circulate from one environmental compartment to another through the food chain, causing harm along the way. Most studies that evaluated the toxicity of these substances considered the effects of a single drug, but observations indicated the presence of drug mixtures, hence the need for further evaluation of the effects of drug–drug interactions—including synergistic and additive effects—for environmental sustainability. The presence of ACs in several environmental compartments at quantifiable quantities was discovered in this investigation, indicating the potential for ecosystem injury as a result of bioaccumulation, bioconcentration, and biomagnification through the food chain. This necessitates further research on the subject in order to ensure a healthier environment.

Pharmacodynamics of Moxifloxacin, Meropenem, Caspofungin and their Combinations Against In Vitro Polymicrobial Inter-kingdom Biofilms

Biofilms colonize medical devices and are often recalcitrant to antibiotics. Inter-kingdom biofilms, when at least a bacterium and a fungus are co-isolated, increase the likelihood of therapeutic failures. In this work, a three-species in vitro biofilm model including S. aureus , E. coli and C. albicans was used to study the activity of the antibiotics moxifloxacin and meropenem, the antifungal caspofungin, and combinations of them against inter-kingdom biofilms. The culturable cells and total biomass were evaluated to determine the pharmacodynamic parameters of the drug response for the incubation with the drugs alone. The synergic or antagonistic effects (increased/decreased effects) of the combination of drugs were analysed with the highest single agent method. Biofilms were imaged in confocal microscopy after live/dead staining. The drugs had limited activity when used alone against single-, dual- or three-species biofilms. When used in combination, additive effects were observed against single- or dual-species biofilms, and increased effects (synergy) against biomass of three-species biofilms. In addition, the two antibiotics showed different patterns, moxifloxacin being more active when targeting S. aureus and meropenem when targeting E. coli . All these observations were confirmed by confocal microscopy images. Our findings highlight the interest in combining caspofungin with antibiotics against inter-kingdom biofilms.