Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• MeSH
• Diet, High-Fat * MeSH
• Insulin Resistance MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Obesity * chemically induced   MeSH
• Pregnane X Receptor * metabolism   genetics   MeSH
• Fungicides, Industrial * toxicity   MeSH
• Triazoles * toxicity   MeSH
• Triglycerides blood   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Fatty Liver * chemically induced   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Global obesity rates have risen dramatically, now exceeding deaths from starvation. Metabolic and bariatric surgery (MBS), initially for severe obesity (BMI ≥35 kg/m2), is performed globally over 500 000 times annually, offering significant metabolic benefits beyond weight loss. However, varying eligibility criteria globally impact patient care and healthcare resources. Updated in 2022, ASMBS and IFSO guidelines aim to standardise MBS indications, reflecting current understanding and emphasising comprehensive preoperative assessments. Yet, clinical variability persists, necessitating consensus-based recommendations. This modified Delphi study engaged 45 global experts to establish consensus on perioperative management in MBS. Experts selected from bariatric societies possessed expertise in MBS and participated in a two-round Delphi protocol. Consensus was achieved on 90 of 169 statements (53.3%), encompassing multidisciplinary team composition, patient selection criteria, preoperative testing, and referral pathways. The agreement highlighted the critical role of comprehensive preoperative assessments and the integration of healthcare professionals in MBS. These findings offer essential insights to standardise perioperative practices and advocate for evidence-based guidelines in MBS globally. The study underscores the need for unified protocols to optimise outcomes and guide future research in MBS.

• MeSH
• Bariatric Surgery * standards   methods   MeSH
• Delphi Technique * MeSH
• Consensus * MeSH
• Humans MeSH
• Obesity, Morbid surgery   MeSH
• Preoperative Care * standards   methods   MeSH
• Patient Selection MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

• MeSH
• Antioxidants metabolism   MeSH
• Bioaccumulation MeSH
• Environmental Pollutants toxicity   MeSH
• Humans MeSH
• Oxidative Stress * drug effects   MeSH
• Metals, Heavy * toxicity   MeSH
• Environmental Exposure adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain. INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain.

• MeSH
• Aggression physiology   MeSH
• Adult MeSH
• Feces * microbiology   chemistry   MeSH
• Impulsive Behavior * physiology   MeSH
• Fatty Acids, Volatile analysis   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Gastrointestinal Microbiome * physiology   MeSH
• Tryptophan blood   metabolism   MeSH
• Criminals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The soil microbiota exhibits an important function in the ecosystem, and its response to climate change is of paramount importance for sustainable agroecosystems. The macronutrients, micronutrients, and additional constituents vital for the growth of plants are cycled biogeochemically under the regulation of the soil microbiome. Identifying and forecasting the effect of climate change on soil microbiomes and ecosystem services is the need of the hour to address one of the biggest global challenges of the present time. The impact of climate change on the structure and function of the soil microbiota is a major concern, explained by one or more sustainability factors around resilience, reluctance, and rework. However, the past research has revealed that microbial interventions have the potential to regenerate soils and improve crop resilience to climate change factors. The methods used therein include using soil microbes' innate capacity for carbon sequestration, rhizomediation, bio-fertilization, enzyme-mediated breakdown, phyto-stimulation, biocontrol of plant pathogens, antibiosis, inducing the antioxidative defense pathways, induced systemic resistance response (ISR), and releasing volatile organic compounds (VOCs) in the host plant. Microbial phytohormones have a major role in altering root shape in response to exposure to drought, salt, severe temperatures, and heavy metal toxicity and also have an impact on the metabolism of endogenous growth regulators in plant tissue. However, shelf life due to the short lifespan and storage time of microbial formulations is still a major challenge, and efforts should be made to evaluate their effectiveness in crop growth based on climate change. This review focuses on the influence of climate change on soil physico-chemical status, climate change adaptation by the soil microbiome, and its future implications.

• MeSH
• Ecosystem MeSH
• Climate Change * MeSH
• Microbiota * MeSH
• Soil chemistry   MeSH
• Soil Microbiology * MeSH
• Plant Growth Regulators metabolism   MeSH
• Crops, Agricultural microbiology   growth & development   MeSH
• Agriculture methods   MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The honeybee (Apis mellifera) is a key pollinator critical to global agriculture, facing threats from various stressors, including the ectoparasitic Varroa mite (Varroa destructor). Previous studies have identified shared bacteria between Varroa mites and honeybees, yet it remains unclear if these bacteria assemble similarly in both species. This study builds on existing knowledge by investigating co-occurrence patterns in the microbiomes of both Varroa mites and honeybees, shedding light on potential interactions. Leveraging 16S rRNA datasets, we conducted co-occurrence network analyses, explored Core Association Networks (CAN) and assess network robustness. Comparative network analyses revealed structural differences between honeybee and mite microbiomes, along with shared core features and microbial motifs. The mite network exhibited lower robustness, suggesting less resistance to taxa extension compared to honeybees. Furthermore, analyses of predicted functional profiling and taxa contribution revealed that common central pathways in the metabolic networks have different taxa contributing to Varroa mites and honeybee microbiomes. The results show that while both microbial systems exhibit functional redundancy, in which different taxa contribute to the functional stability and resilience of the ecosystem, there is evidence for niche specialization resulting in unique contributions to specific pathways in each part of this host-parasite system. The specificity of taxa contribution to key pathways offers targeted approaches to Varroa microbiome management and preserving honeybee microbiome. Our findings provide valuable insights into microbial interactions, aiding farmers and beekeepers in maintaining healthy and resilient bee colonies amid increasing Varroa mite infestations.

• MeSH
• Bacteria * classification   genetics   isolation & purification   MeSH
• Microbiota * MeSH
• RNA, Ribosomal, 16S genetics   MeSH
• Varroidae * microbiology   MeSH
• Bees microbiology   parasitology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.

• MeSH
• Aldehyde Dehydrogenase deficiency   genetics   MeSH
• Biomarkers * urine   MeSH
• Child MeSH
• Epilepsy urine   MeSH
• Infant MeSH
• 2-Aminoadipic Acid urine   analogs & derivatives   MeSH
• Pipecolic Acids * urine   MeSH
• Humans MeSH
• Lysine deficiency   urine   MeSH
• Aldehyde Dehydrogenase, Mitochondrial deficiency   genetics   MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Pyridoxine deficiency   urine   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.

• MeSH
• Energy Metabolism * physiology   MeSH
• Humans MeSH
• Metabolic Networks and Pathways * physiology   MeSH
• Brain * metabolism   MeSH
• Nerve Net * metabolism   MeSH
• Neurons * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) may be as high as 38% in the adult population with potential serious complications, multiple comorbidities and a high socioeconomic burden. However, there is a general lack of awareness and knowledge about MASLD and its progressive stages (metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis). Therefore, MASLD is still far underdiagnosed. The 'Global Research Initiative for Patient Screening on MASH' (GRIPonMASH) consortium focuses on this unmet public health need. GRIPonMASH will help (primary) healthcare providers to implement a patient care pathway, as recommended by multiple scientific societies, to identify patients at risk of severe MASLD and to raise awareness. Furthermore, GRIPonMASH will contribute to a better understanding of the pathophysiology of MASLD and improved identification of diagnostic and prognostic markers to detect individuals at risk. METHODS: This is a prospective multicentre observational study in which 10 000 high-risk patients (type 2 diabetes mellitus, obesity, metabolic syndrome or hypertension) will be screened in 10 European countries using at least two non-invasive tests (Fibrosis-4 index and FibroScan). Blood samples and liver biopsy material will be collected and biobanked, and multiomics analyses will be conducted. ETHICS AND DISSEMINATION: The study will be conducted in compliance with this protocol and applicable national and international regulatory requirements. The study initiation package is submitted at the local level. The study protocol has been approved by local medical ethical committees in all 10 participating countries. Results will be made public and published in scientific, peer-reviewed, international journals and at international conferences. REGISTRATION DETAILS: NCT05651724, registration date: 15 Dec 2022.

• MeSH
• Diabetes Mellitus, Type 2 complications   MeSH
• Liver Cirrhosis diagnosis   MeSH
• Humans MeSH
• Metabolic Syndrome complications   MeSH
• Multicenter Studies as Topic MeSH
• Non-alcoholic Fatty Liver Disease * diagnosis   MeSH
• Mass Screening * methods   MeSH
• Prospective Studies MeSH
• Research Design MeSH
• Fatty Liver * diagnosis   epidemiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH

Across the tree of life, DNA damage response (DDR) proteins play a pivotal, yet dichotomous role in organismal development and evolution. Here, we present a comprehensive analysis of 432 DDR proteins encoded by 68 genomes, including that of Nucleospora cyclopteri, an intranuclear microsporidia sequenced in this study. We compared the DDR proteins encoded by these genomes to those of humans to uncover the DNA repair-ome across phylogenetically distant eukaryotes. We also performed further analyses to understand if organismal complexity and lifestyle play a role in the evolution of DDR protein length and conserved domain architecture. We observed that the genomes of extreme parasites such as Paramicrocytos, Giardia, Spironucleus, and certain microsporidian lineages encode the smallest eukaryotic repertoire of DDR proteins and that pathways involved in modulation of nucleotide pools and nucleotide excision repair are the most preserved DDR pathways in the eukaryotic genomes analysed here. We found that DDR and DNA repair proteins are consistently longer than housekeeping and metabolic proteins. This is likely due to the higher number of physical protein-protein interactions which DDR proteins are involved. We find that although DNA repair proteins are generally longer than housekeeping proteins, their functional domains occupy a relatively smaller footprint. Notably, this pattern holds true across diverse organisms and shows no dependence on either lifestyle or mitochondrial status. Finally, we observed that unicellular organisms harbour proteins that are tenfold longer than their human homologues, with the extra amino acids forming interdomain regions with a clearly novel albeit undetermined function.

• MeSH
• Eukaryota * genetics   MeSH
• Phylogeny MeSH
• Humans MeSH
• Microsporidia genetics   MeSH
• Evolution, Molecular * MeSH
• DNA Repair * MeSH
• DNA Damage * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH