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Life Science Alliance Sep 2024Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to...
Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs), and the HIF-1α subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46 ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46 ILC1s but a concomitant rise in neutrophils and Ly6C macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.
Topics: Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Natural Cytotoxicity Triggering Receptor 1; Mice; Colitis; Fibrosis; Mice, Knockout; Lymphocytes; Intestinal Mucosa; Inflammation; Mice, Inbred C57BL; Chronic Disease; Immunity, Innate; Signal Transduction; Disease Models, Animal; Male; Intestines; Antigens, Ly
PubMed: 38876796
DOI: 10.26508/lsa.202402593 -
International Journal For Parasitology.... Jun 2024Cryptosporidium parvum is a waterborne and foodborne zoonotic protozoan parasite, a causative agent of moderate to severe diarrheal diseases in humans and animals....
Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite.
Cryptosporidium parvum is a waterborne and foodborne zoonotic protozoan parasite, a causative agent of moderate to severe diarrheal diseases in humans and animals. However, fully effective treatments are unavailable for medical and veterinary uses. There is a need to explore new drug targets for potential development of new therapeutics. Because C. parvum relies on anaerobic metabolism to produce ATP, fermentative enzymes in this parasite are attractive targets for exploration. In this study, we investigated the ethanol-fermentation in the parasite and characterized the basic biochemical features of a bacterial-type bifunctional aldehyde/alcohol dehydrogenase, namely CpAdhE. We also screened 3892 chemical entries from three libraries and identified 14 compounds showing >50% inhibition on the enzyme activity of CpAdhE. Intriguingly, antifungal imidazoles and unsaturated fatty acids are the two major chemical groups among the top hits. We further characterized the inhibitory kinetics of selected imidazoles and unsaturated fatty acids on CpAdhE. These compounds displayed lower micromolar activities on CpAdhE (i.e., IC values ranging from 0.88 to 11.02 μM for imidazoles and 8.93 to 35.33 μM for unsaturated fatty acids). Finally, we evaluated the in vitro anti-cryptosporidial efficacies and cytotoxicity of three imidazoles (i.e., tioconazole, miconazole and isoconazole). The three antifungal imidazoles exhibited lower micromolar efficacies against the growth of C. parvum in vitro (EC values ranging from 4.85 to 10.41 μM and selectivity indices ranging from 5.19 to 10.95). The results provide a proof-of-concept data to support that imidazoles are worth being further investigated for potential development of anti-cryptosporidial therapeutics.
PubMed: 38875756
DOI: 10.1016/j.ijpddr.2024.100551 -
Parasite (Paris, France) 2024The emergence of pandemics with dramatic consequences for human health has obscured endemic diseases that continue to pose a problem for human and animal health in... (Review)
Review
The emergence of pandemics with dramatic consequences for human health has obscured endemic diseases that continue to pose a problem for human and animal health in several regions of the world. Among these diseases, cystic echinococcosis, a zoonotic parasitic infection caused by a group of cestodes, Echinococcus granulosus sensu lato, remains a real human and animal health problem in several regions of the world, including the Mediterranean Basin. Despite the implementation of a number of governmental control programmes using several tools (dog treatment, meat inspection, etc.), this infection is still highly prevalent in North Africa. Here we present a review of the epidemiology of cystic echinococcosis in Tunisia, an analysis of the constraints limiting the effectiveness of the control programmes implemented, and finally argue for the use of the One Health framework to improve the effectiveness of future programmes.
Topics: Tunisia; Humans; Animals; Echinococcosis; Echinococcus granulosus; One Health; Zoonoses; Dogs; Prevalence; Dog Diseases
PubMed: 38874552
DOI: 10.1051/parasite/2024029 -
Animal Models and Experimental Medicine Jun 2024Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as...
BACKGROUND
Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K kinase in the MAPK signaling pathway activated by stressors and triggers downstream biological effects such as inflammation and apoptosis; therefore, inhibition of ASK1 kinase activity can protect cells from pathological injury. In this study, we designed and synthesized a novel selective ASK1 inhibitor, CS17919, and investigated its pharmacological effects in various animal models of metabolic injury.
METHODS
First, we validated the ability of CS17919 to inhibit ASK1 in vitro and then tested the safety profile of CS17919 in cell lines compared with Selonsertib (GS-4997), a phase III ASK1 inhibitor. We then conducted pharmacokinetic (PK) studies in mice. Finally, we tested the in vivo efficacy of CS17919 in murine models of chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH).
RESULTS
Compared to GS-4997, CS17919 demonstrated comparable inhibition of ASK1 in vitro, exhibited lower toxicity, and provided greater protection in palmitic acid-treated LO2 cells. CS17919 also showed pronounced pharmacokinetic properties such as a high plasma concentration. In the unilateral ureteral obstruction model (UUO), CS17919 and GS-4997 preserved kidney function and showed a non-significant tendency to alleviate kidney fibrosis. In the diabetic kidney disease (DKD) model, CS17919 significantly improved serum creatinine and glomerular sclerosis. In the NASH model, the combination of CS17919 and a THRβ agonist (CS27109) was found to significantly improve liver inflammation and substantially reduced liver fibrosis.
CONCLUSIONS
CS17919 showed cell protective, anti-inflammatory, and antifibrotic effects in vitro and in vivo, suggesting its therapeutic potential for metabolic-related kidney and liver diseases.
PubMed: 38873818
DOI: 10.1002/ame2.12437 -
Conservation Physiology 2024Thermal stress can influence the recovery of fish released after capture. Vitality assessments using reflex and behavioural responses require that responses can be...
Thermal stress can influence the recovery of fish released after capture. Vitality assessments using reflex and behavioural responses require that responses can be observed reliably, independent of temperature. Here, we tested whether reflex and behavioural impairment and survival of beam-trawled and discarded European plaice () are independent from seasonal air and water temperature deviations. In total, 324 beam-trawled plaice ( = 196 in summer and = 128 in winter) were exposed to two air temperature treatments and two water treatments (i.e. modified and ambient temperatures for both). The modified treatments (i.e. cooled in summer, warmed in winter) represent the thermal shock a fish may experience when being returned to the water. All reflexes and tested behaviours were affected by ambient temperature, with high impairment noted in summer. None of the reflexes were affected by temperature shocks alone, only body flex was. Body flex was highly impaired under every exposure combination. Fish size and duration of air exposure further influenced impairment of reflexes such as head complex and tail grab. More generally, post-release survival was assessed as 21% [95% CI: 16-28%] in summer and 99% [97-100%] in winter. Beam trawling in summer is likely to induce high reflex impairment and mortality in discarded plaice, and therefore spatial-temporal mitigation approaches should be prioritized over control of on-board temperatures.
PubMed: 38873635
DOI: 10.1093/conphys/coae036 -
Frontiers in Immunology 2024Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current...
Newcastle disease virus vector-based SARS-CoV-2 vaccine candidate AVX/COVID-12 activates T cells and is recognized by antibodies from COVID-19 patients and vaccinated individuals.
INTRODUCTION
Several effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and implemented in the population. However, the current production capacity falls short of meeting global demand. Therefore, it is crucial to further develop novel vaccine platforms that can bridge the distribution gap. AVX/COVID-12 is a vector-based vaccine that utilizes the Newcastle Disease virus (NDV) to present the SARS-CoV-2 spike protein to the immune system.
METHODS
This study aims to analyze the antigenicity of the vaccine candidate by examining antibody binding and T-cell activation in individuals infected with SARS-CoV-2 or variants of concern (VOCs), as well as in healthy volunteers who received coronavirus disease 2019 (COVID-19) vaccinations.
RESULTS
Our findings indicate that the vaccine effectively binds antibodies and activates T-cells in individuals who received 2 or 3 doses of BNT162b2 or AZ/ChAdOx-1-S vaccines. Furthermore, the stimulation of T-cells from patients and vaccine recipients with AVX/COVID-12 resulted in their proliferation and secretion of interferon-gamma (IFN-γ) in both CD4+ and CD8+ T-cells.
DISCUSSION
The AVX/COVID-12 vectored vaccine candidate demonstrates the ability to stimulate robust cellular responses and is recognized by antibodies primed by the spike protein present in SARS-CoV-2 viruses that infected patients, as well as in the mRNA BNT162b2 and AZ/ChAdOx-1-S vaccines. These results support the inclusion of the AVX/COVID-12 vaccine as a booster in vaccination programs aimed at addressing COVID-19 caused by SARS-CoV-2 and its VOCs.
Topics: Humans; COVID-19; SARS-CoV-2; Antibodies, Viral; Newcastle disease virus; COVID-19 Vaccines; Spike Glycoprotein, Coronavirus; Lymphocyte Activation; Adult; Female; Male; Middle Aged; T-Lymphocytes; BNT162 Vaccine; Vaccination; Genetic Vectors; Interferon-gamma
PubMed: 38873610
DOI: 10.3389/fimmu.2024.1394114 -
Food Science & Nutrition Jun 2024The use of animal manure to fertilize soil is an emerging concern contributing to the transfer of antimicrobial-resistant pathogens to vegetables. Hence, assessing...
The use of animal manure to fertilize soil is an emerging concern contributing to the transfer of antimicrobial-resistant pathogens to vegetables. Hence, assessing antimicrobial susceptibility profile of in vegetable farms is essential to design appropriate interventions against antimicrobial resistance (AMR) in the food chain. This study assessed antimicrobial resistance profile and associated genetic markers among isolated from vegetable farms fertilized with animal manure in Addis Ababa, Ethiopia. A total of 1044 samples were collected using convenience sampling: soil ( = 271), manure ( = 375), and vegetables ( = 398) from 81 vegetable farms in Addis Ababa, Ethiopia. Antimicrobial susceptibility test was conducted for 100 isolates and antimicrobial resistance genes (ARGs) were tested by polymerase chain reaction (PCR). Of the 1044 collected samples, 25.3% were positive for , with significantly higher prevalence in the manure sample and samples collected from Akaki Kality sub-city ( < .05). The highest resistance rate was recorded for tetracycline (72%), followed by streptomycin (63%), and sulfamethoxazole +trimethoprim (56%). Multidrug resistance was detected in 61% of the isolates. The (76.9%), (65.4%), (), (58.3%), and (51.7%) were the commonly detected resistance genes. The current study showed a high burden of antimicrobial resistance among isolated from manure-amended vegetable farms, with potential of playing a significant role in the dissemination of antimicrobial resistance in the food chain. Efforts should be made to reduce the burden of resistant organisms and ARGs through prudent use of antimicrobials in livestock and application of appropriate composting techniques before using manure as fertilizer.
PubMed: 38873492
DOI: 10.1002/fsn3.4071 -
Frontiers in Pharmacology 2024Dim light at night contributes to neurodegenerative diseases by causing neuroinflammation. In the central nervous system, the activation of microglia is a significant...
OBJECTIVES
Dim light at night contributes to neurodegenerative diseases by causing neuroinflammation. In the central nervous system, the activation of microglia is a significant contributor to neuroinflammation. Therefore, there is an urgent need to find an intervention to treat the neuroinflammatory response caused by dim light at night. Melatonin is a rhythmic hormone whose synthesis is suppressed during the day. In this study, we attempt to explore whether and how melatonin improves hippocampal neuroinflammation in mice exposed to dim blue light at night.
MATERIALS AND METHODS
, a total of 36 male C57BL6/J mice that exposed to no light at night, dim blue light at night, and dim blue light at night with melatonin treatment. , the corticosterone-induced BV2 cells with or without melatonin treatment were used.
RESULTS
Both and experiments showed melatonin treatment significantly reduced dim blue light -induced hippocampal microglial activation and the expression of inflammatory factors IL-1β and TNF-α. This improved effect of melatonin is related to its receptor MT2 rather than MT1. The MT2 blockers significantly increased mRNA levels of M1-type activation marker CD86 and inflammatory cytokines IL-1β and TNF-α in melatonin-treated BV2 cells. Binding of melatonin to its receptor MT2 downregulated the expression of inflammatory proteins P-P65 and NLRP3, consequently inhibited the CD80 expression and M1-type activation in microglia. Furthermore, consistent with the decrease in microglial activation and inflammatory response after melatonin treatment, we also observed a reduction in hippocampal neuron loss and damage to the HT22 cells.
CONCLUSION
Our findings suggested that melatonin may regulate microglial polarization through MT2/NF-kB-NLRP3 pathway and improves dim blue light -induced hippocampal neuroinflammation in mice.
PubMed: 38873431
DOI: 10.3389/fphar.2024.1416350 -
Frontiers in Molecular Neuroscience 2024Phagocytes maintain homeostasis in a healthy brain. Upon injury, they are essential for repairing damaged tissue, recruiting other immune cells, and releasing cytokines... (Review)
Review
Phagocytes maintain homeostasis in a healthy brain. Upon injury, they are essential for repairing damaged tissue, recruiting other immune cells, and releasing cytokines as the first line of defense. However, there seems to be a delicate balance between the beneficial and detrimental effects of their activation in a seizing brain. Blocking the infiltration of peripheral phagocytes (macrophages) or their depletion can partially alleviate epileptic seizures and prevent the death of neurons in experimental models of epilepsy. However, the depletion of resident phagocytes in the brain (microglia) can aggravate disease outcomes. This review describes the role of resident microglia and peripheral infiltrating monocytes in animal models of acutely triggered seizures and epilepsy. Understanding the roles of phagocytes in ictogenesis and the time course of their activation and involvement in epileptogenesis and disease progression can offer us new biomarkers to identify patients at risk of developing epilepsy after a brain insult, as well as provide novel therapeutic targets for treating epilepsy.
PubMed: 38873242
DOI: 10.3389/fnmol.2024.1404022 -
International Journal For Parasitology.... Aug 2024To investigate infection of fish in the river system of Xinjiang (China), individuals were isolated from specimens of . Morphological characterization and phylogenetic...
To investigate infection of fish in the river system of Xinjiang (China), individuals were isolated from specimens of . Morphological characterization and phylogenetic analysis based on rDNA locus revealed that the gyrodactylids belong to new species. n. sp. differs significantly in the morphology of the haptoral structures from 12 known species of found in fishes of the subfamily Schizothoracinae. In particular, n. sp. has a relatively short dorsal bar with thick and large ends, flat and straight hamuli roots, and small ventral bar processes. Furthermore, . n. sp. is the only representative of found on Using the BLASTn search of rDNA sequences in GenBank and the Bayesian Information and Maximum Likelihood methods, we constructed phylogenetic trees for n. sp. As a result, our studies clearly identified that n. sp. was the first monogenean isolated from . and a new species belonged to the subgenus .
PubMed: 38873216
DOI: 10.1016/j.ijppaw.2024.100949