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Environmental Pollution (Barking, Essex... Jul 2024Pyraclostrobin, a typical representative of strobilurin fungicides, is extensively used in agriculture to control fungi and is often detected in water bodies and food....
Pyraclostrobin, a typical representative of strobilurin fungicides, is extensively used in agriculture to control fungi and is often detected in water bodies and food. However, the comprehensive toxicological molecular mechanism of pyraclostrobin requires further study. To assess the toxic effects and underlying mechanisms of pyraclostrobin on aquatic organisms, zebrafish embryos were exposed to pyraclostrobin (20, 40, and 60 μg/L) until 96 h post fertilization (hpf). These results indicated that exposure to pyraclostrobin induces morphological alterations, including spinal curvature, shortened body length, and smaller eyes. Furthermore, heart developmental malformations, such as pericardial edema and bradycardia, were observed. This indicated severe cardiotoxicity induced by pyraclostrobin in zebrafish embryos, which was confirmed by the dysregulation of genes related to heart development. Besides, our findings also demonstrated that pyraclostrobin enhanced the contents of reactive oxygen species (ROS) and malondialdehyde (MDA), up-regulated catalase (CAT) activity, but inhibited superoxide dismutase (SOD) activity. Subsequently, the NF-κb signaling pathway was further studied, and the results indicated that the up-regulation of tnf-α, tlr-4, and myd88 activated the NF-κb signaling pathway and up-regulated the relative expression level of pro-inflammatory cytokines, such as cc-chemokine, ifn-γ, and cxcl-clc. Collectively, this study revealed that pyraclostrobin exposure induces developmental toxicity and cardiotoxicity, which may result from a combination of oxidative stress and inflammatory responses. These findings provide a basis for continued evaluation of the effects and ecological risks of pyraclostrobin on the early development of aquatic organisms.
PubMed: 38960114
DOI: 10.1016/j.envpol.2024.124490 -
Pharmacological Research Jul 2024Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound...
Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound isolated from fungus of marine sponge origin, which has antibacterial, anti-inflammatory, lipid-lowering, and weight loss effects. Whether EQST has anti-atherosclerotic activity has not been reported. In this study, we revealed that EQST displayed anti- atherosclerosis effects through inhibiting macrophage inflammatory response, lipid uptake and foam cell formation in vitro, and finally ameliorated high-fat diet (HFD)-induced atherosclerosis in AopE mice in vivo. Mechanistically, EQST directly bound to STAT3 with high-affinity by forming hydrophobic bonds at GLN247 and GLN326 residues, as well as hydrogen bonds at ARG325 and THR346 residues. EQST interacted with STAT3 physically, and functionally inhibited the transcription activity of STAT3, thereby regulating atherosclerosis. Therefore, these results supports EQST as a candidate for developing anti-atherosclerosis therapeutic agent.
PubMed: 38960011
DOI: 10.1016/j.phrs.2024.107289 -
Kidney International Jul 2024Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects...
Patient navigators enable adult patients to circumnavigate complex health systems, improving access to health care and outcomes. Here, we aimed to evaluate the effects of a patient navigation program in children with chronic kidney disease (CKD). In this multi-center, randomized controlled trial, we randomly assigned children (aged 0-16 years) with CKD stages 1-5 (including children on dialysis or with kidney transplants), from low socioeconomic status backgrounds, and/or residing in remote areas, to receive patient navigation at randomization (immediate) or at six months (waitlist). The primary outcome was self-rated health (SRH) of participating children at six months, using intention to treat analysis. Secondary outcomes included caregivers' SRH and satisfaction with health care, children's quality of life, hospitalizations, and missed school days. Repeated measures of the primary outcome from baseline to six months were analyzed using cumulative logit mixed effects models. Semi-structured interviews were thematically evaluated. Of 398 screened children, 162 were randomized (80 immediate and 82 waitlist); mean age (standard deviation) of 8.8 (4.8) years with 64.8% male. SRH was not significantly different between the immediate and wait-listed groups at six months. There were also no differences across all secondary outcomes between the two groups. Caregivers' perspectives were reflected in seven themes: easing mental strain, facilitating care coordination, strengthening capacity to provide care, reinforcing care collaborations, alleviating family tensions, inability to build rapport and unnecessary support. Thus, in children with CKD, self-rated health may not improve in response to a navigator program, but caregivers gained skills related to providing and accessing care.
PubMed: 38959996
DOI: 10.1016/j.kint.2024.05.031 -
Cell Jun 2024The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an...
The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPR) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPR signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPR activation. We also find that the germline tissue itself is essential for UPR signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.
PubMed: 38959891
DOI: 10.1016/j.cell.2024.06.010 -
Cell Jun 2024Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified...
Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.
PubMed: 38959890
DOI: 10.1016/j.cell.2024.06.001 -
Cell Metabolism Jul 2024Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin...
Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.
Topics: Humans; Insulin Secretion; Proteomics; Diabetes Mellitus, Type 2; Male; Female; Insulin; Islets of Langerhans; Middle Aged; Nutrients; Adult; Glucose; Aged; Fatty Acids
PubMed: 38959864
DOI: 10.1016/j.cmet.2024.06.001 -
Journal of Psychiatric Research Jun 2024Facial mimicry serves as an evolutionarily rooted important interpersonal communication process that touches on the concepts of socialization and empathy. Facial...
Facial mimicry serves as an evolutionarily rooted important interpersonal communication process that touches on the concepts of socialization and empathy. Facial electromyography (EMG) of the corrugator muscle and the zygomaticus muscle was recorded while male forensic psychopathic patients and controls watched morphed angry or happy facial expressions. We tested the hypothesis that psychopathic patients would show weaker short latency facial mimicry (that is, within 600 ms after stimulus onset) than controls. Exclusively in the group of 20 psychopathic patients, we tested in a placebo-controlled crossover within-subject design the hypothesis that oxytocin would enhance short-latency facial mimicry. Compared with placebo, we found no oxytocin-related significant short-latency responses of the corrugator and the zygomaticus. However, compared with 19 normal controls, psychopathic patients in the placebo condition showed significantly weaker short-latency zygomaticus responses to happy faces, while there was a trend toward significantly weaker short-latency corrugator responses to angry faces. These results are consistent with a recent study of facial EMG responses in adolescents with psychopathic traits. We therefore posit a lifetime developmental deficit in psychopathy pertaining short-latency mimicry of emotional facial expressions. Ultimately, this deficit in mimicking angry and happy expressions may hinder the elicitation of empathy, which is known to be impaired in psychopathy.
PubMed: 38959825
DOI: 10.1016/j.jpsychires.2024.06.032 -
Clinical Neurology and Neurosurgery Jun 2024Chemotherapy in brain tumors is tailored based on tumor type, grade, and molecular markers, which are crucial for predicting responses and survival outcomes. This review... (Review)
Review
Chemotherapy in brain tumors is tailored based on tumor type, grade, and molecular markers, which are crucial for predicting responses and survival outcomes. This review summarizes the role of chemotherapy in gliomas, glioneuronal and neuronal tumors, ependymomas, choroid plexus tumors, medulloblastomas, and meningiomas, discussing standard treatment protocols and recent developments in targeted therapies.Furthermore, the studies reporting the integration of MRI-based radiomics and deep learning models for predicting treatment outcomes are reviewed. Advances in MRI-based radiomics and deep learning models have significantly enhanced the prediction of chemotherapeutic benefits, survival prediction following chemotherapy, and differentiating tumor progression with psuedoprogression. These non-invasive techniques offer valuable insights into tumor characteristics and treatment responses, facilitating personalized therapeutic strategies. Further research is warranted to refine these models and expand their applicability across different brain tumor types.
PubMed: 38959786
DOI: 10.1016/j.clineuro.2024.108409 -
Journal of Plant Physiology Jun 2024Cassava (Manihot esculenta Crantz) produces edible roots, a major carbohydrate source feeding more than 800 million people in Africa, Latin America, Oceania and Asia....
Biochemical characterisation of a cassava (Manihot esculenta crantz) diversity panel for post-harvest physiological deterioration; metabolite involvement and environmental influence.
Cassava (Manihot esculenta Crantz) produces edible roots, a major carbohydrate source feeding more than 800 million people in Africa, Latin America, Oceania and Asia. Post-harvest physiological deterioration (PPD) renders harvested cassava roots unpalatable and unmarketable. Decades of research on PPD have elucidated several genetic, enzymatic and metabolic processes involved. Breeding populations were established to enable verification of robust biomarkers for PPD resistance. For comparison, these PPD populations have been cultivated concurrently with diversity population for carotenoid (β-carotene) content. Results highlighted a significant variation of the chemotypes due to environmental factors. Less than 3% of the detected molecular features showed consistent trends between the two harvest years and were putatively identified as phenylpropanoid derived compounds (e.g. caffeoyl rutinoside). The data corroborated that ∼20 μg β-carotene/g DW can reduced the PPD response of the cassava roots to a score of ∼1. Correlation analysis showed a significant correlation of β-carotene content at harvest to PPD response (R -0.55). However, the decrease of β-carotene over storage was not significantly correlated to initial content or PPD response. Volatile analysis observed changes of apocarotenoids derived from β-carotene, lipid oxidation products (alkanes, alcohols and carbonyls and esters) and terpenes. The majority of these volatiles (>90%) showed no significant correlation to β-carotene or PPD. Observed data indicated an increase (∼2-fold) of alkanes in varieties with β-carotene >10 μg/g DW and a decrease (∼60%) in varieties with less β-carotene. Fatty acid methyl esters with a chain length > C9 were detected solely after storage and show lower levels in varieties with higher β-carotene content. In combination with correlation values to PPD (R ∼0.3; P-value >0.05), the data indicated a more efficient ROS quenching mechanism in PPD resistant varieties.
PubMed: 38959754
DOI: 10.1016/j.jplph.2024.154303 -
Current Opinion in Chemical Biology Jul 2024HO signals trigger adaptive responses affecting cell division, differentiation, migration, and survival. These signals are transduced by selective oxidation of cysteines... (Review)
Review
HO signals trigger adaptive responses affecting cell division, differentiation, migration, and survival. These signals are transduced by selective oxidation of cysteines on specific target proteins, with redox-sensitive cysteines now identified in many proteins, including both kinases and phosphatases. Assessing the contribution of these oxidation events to cell signalling presents several challenges including understanding how and when the selective oxidation of specific proteins takes place in vivo. In recent years, a combination of biochemical, structural, genetic, and computational approaches in fungi, plants, and animals have revealed different ways in which thiol peroxidases (peroxiredoxins) are bypassed or utilised in relaying these signals. Together, these mechanisms provide a conceptual framework for selectively oxidising proteins that will further advance understanding of how redox modifications contribute to health and disease.
PubMed: 38959751
DOI: 10.1016/j.cbpa.2024.102496