-
Poultry Science Jun 2024Submerged cultivation using low-value agro-industrial side streams allows large-scale and efficient production of fungal mycelia, which has a high nutritional value. As...
Submerged cultivation using low-value agro-industrial side streams allows large-scale and efficient production of fungal mycelia, which has a high nutritional value. As the dietary properties of fungal mycelia in poultry are largely unknown, the present study aimed to investigate the effect of feeding a Pleurotus sapidus (PSA) mycelium as a feed supplement on growth performance, composition of the cecal microbiota and several physiological traits including gut integrity, nutrient digestibility, liver lipids, liver transcriptome and plasma metabolome in broilers. 72 males, 1-day-old Cobb 500 broilers were randomly assigned to 3 different groups and fed 3 different adequate diets containing either 0% (PSA-0), 2.5% (PSA-2.5) and 5% (PSA-5.0) P. sapidus mycelium in a 3-phase feeding system for 35 d. Each group consisted of 6 cages (replicates) with 4 broilers/cage. Body weight gain, feed intake and feed:gain ratio and apparent ileal digestibility of crude protein, ether extract and amino acids were not different between groups. Metagenomic analysis of the cecal microbiota revealed no differences between groups, except that one α-diversity metric (Shannon index) and the abundance of 2 low-abundance bacterial taxa (Clostridia UCG 014, Eubacteriales) differed between groups (P < 0.05). Concentrations of total and individual short-chain fatty acids in the cecal digesta and concentrations of plasma lipopolysaccharide and mRNA levels of proinflammatory genes, tight-junction proteins, and mucins in the cecum mucosa did not differ between groups. None of the plasma metabolites analyzed using targeted-metabolomics differed across the groups. Hepatic transcript profiling revealed a total of 144 transcripts to be differentially expressed between group PSA-5.0 and group PSA-0 but none of these genes was regulated greater 2-fold. Considering either the lack of effects or the very weak effects of feeding the P. sapidus mycelium in the broilers it can be concluded that inclusion of a sustainably produced fungal mycelium in broiler diets at the expense of other feed components has no negative consequences on broilers´ performance and metabolism.
PubMed: 38945001
DOI: 10.1016/j.psj.2024.103975 -
Poultry Science Jun 2024Increased consumption of folic acid is prevalent due to its beneficial effects, but growing evidence emphasizes the side effects pointing to excessive dietary folate...
Nanopore sequencing demonstrates the roles of spermatozoal DNA N6-methyladenine in mediating transgenerational lipid metabolism disorder induced by excessive folate consumpton.
Increased consumption of folic acid is prevalent due to its beneficial effects, but growing evidence emphasizes the side effects pointing to excessive dietary folate intake. The effects of excessive paternal folic acid consumption on offspring and its transgenerational inheritance mechanism have not been elucidated. We hypothesize that excessive folic acid consumption will alter sperm DNA N6-methyladenine (6mA) and 5-methylcytosine (5mC) methylation and heritably influence offspring metabolic homeostasis. Here, we fed roosters either folic acid-control or folic acid-excess diet throughout life. Paternal chronic folic acid excessive supplementation increased hepatic lipogenesis and lipid accumulation but reduced lipolysis both in the roosters and their offspring, which was further confirmed to be induced by one-carbon metabolism inhibition and gene expression alteration associated with the Peroxisome proliferator-activated receptor pathway. Based on the spermatozoal genome-wide DNA methylome identified by Nanopore sequencing, multi-omics association analysis of spermatozoal and hepatic DNA methylome, transcriptome, and metabolome suggested that differential spermatozoal DNA 6mA and 5mC methylation could be involved in regulating lipid metabolism-related gene expression in offspring chickens. This model suggests that sperm DNA N6-methyladenine and 5-methylcytosine methylation were involved in epigenetic transmission and that paternal dietary excess folic acid leads to hepatic lipid accumulation in offspring.
PubMed: 38945000
DOI: 10.1016/j.psj.2024.103953 -
Cell Reports Jun 2024Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with...
Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.
PubMed: 38944837
DOI: 10.1016/j.celrep.2024.114409 -
Cell Reports Jun 2024Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate...
Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate the evolutionary function of VDR by demonstrating that zebrafish Vdr coordinates hepatic and organismal energy homeostasis through antagonistic regulation of nutrient storage and tissue growth. Hepatocyte-specific Vdr impairment increases hepatic lipid storage, partially through acsl4a induction, while simultaneously diminishing fatty acid oxidation and liver growth. Importantly, Vdr impairment exacerbates the starvation-induced hepatic storage of systemic fatty acids, indicating that loss of Vdr signaling elicits hepatocellular energy deficiency. Strikingly, hepatocyte Vdr impairment diminishes diet-induced systemic growth while increasing hepatic and visceral fat in adult fish, revealing that hepatic Vdr signaling is required for complete adaptation to food availability. These data establish hepatocyte Vdr as a regulator of organismal energy expenditure and define an evolutionary function for VDR as a transcriptional effector of environmental nutrient supply.
PubMed: 38944835
DOI: 10.1016/j.celrep.2024.114393 -
NPJ Science of Food Jun 2024Inflammation acts as a dual role in disease initiation and progression, while Cannabis sativa L. (hemp) seeds, known for their abundance of anti-inflammatory...
Inflammation acts as a dual role in disease initiation and progression, while Cannabis sativa L. (hemp) seeds, known for their abundance of anti-inflammatory phytochemicals, present a promising food source. Additionally, fermentation may optimize the food matrix, thereby augmenting its developmental prospects. This study explores the anti-inflammatory potential of hemp seeds fermented with 10 different probiotic strains. Among these, Lactiplantibacillus plantarum fermented hemp seeds (FHS) demonstrated a significant anti-inflammatory ability, accompanied by a reduction in the expression of critical inflammatory markers such as TLR4, NF-κBp65, and iNOS. Moreover, there is a noteworthy dose-dependent inhibition of inflammatory cytokines TNF-α, IL-6, IL-1β, and NO within a concentration range of 50 to 500 µg/mL. Subsequently, metabolomics analysis using UHPLC-QTOF-MS highlighted significant metabolic alterations in FHS compared to raw hemp seeds (RHS). Through multivariate, univariate, and correlation analyses, indolelactic acid (IA) and homovanillic acid (HVA) emerged as the main anti-inflammatory metabolites in FHS. Validation via HPLC confirmed the concentration of IA and HVA in RHS and FHS and both organic acids demonstrated lower IC values for TNF-α, IL-1β, IL-6, IL-18, and NO inhibition, showcasing their potent anti-inflammatory abilities. Furthermore, in vitro gastro-intestinal digestion coupled with the Caco-2 cell monolayer model validates the uptake and bioaccessibility of FHS, further affirming IA and HVA as major anti-inflammatory compounds. Overall, this research sets the stage for the development of novel hemp seed-based products targeting inflammation-associated disorders.
PubMed: 38944646
DOI: 10.1038/s41538-024-00285-8 -
International Journal of Infectious... Jun 2024In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In...
In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In our influenza surveillance during the COVID-19 pandemic, co-infection with SARS-CoV-2 and influenza virus had not been detected; however, in January 2024, we identified three pediatric outpatients co-infected with these viruses: one with SARS-CoV-2 Omicron EG.5 sublineage HK.3 and influenza A(H3N2) and two with SARS-CoV-2 Omicron BA.2.86 sublineage JN.1.5 and influenza A(H1N1)pdm09. We evaluated the susceptibility of SARS-CoV-2 against RNA-dependent RNA polymerase inhibitors (remdesivir and molnupiravir) and 3C-like protease inhibitors (nirmatrelvir and ensitrelvir), and that of influenza viruses against neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and the cap-dependent endonuclease inhibitor baloxavir. All viruses tested were susceptible to these antiviral drugs and did not possess amino acid substitutions associated with reduced antiviral susceptibility. The patients were treated with anti-influenza drugs and did not develop severe symptoms despite the co-infection. Since SARS-CoV-2 and influenza viruses continue to evolve, continuous monitoring of their circulation remains essential to assess public health measures and support clinical management.
PubMed: 38944411
DOI: 10.1016/j.ijid.2024.107134 -
Protein Expression and Purification Jun 2024Peptides are used for diagnostics, therapeutics, and as antimicrobial agents. Most peptides are produced by chemical synthesis, but recombinant production has recently...
Peptides are used for diagnostics, therapeutics, and as antimicrobial agents. Most peptides are produced by chemical synthesis, but recombinant production has recently become an attractive alternative due to the advantages of high titers, less toxic waste and correct folding of tertiary structure. Somatostatin-28 is a peptide hormone that regulates the endocrine system, cell proliferation and inhibits the release of numerous secondary hormones in human body. It is composed of 28 amino acids and has one disulfide bond, which makes it to an optimal model peptide for a whole downstream purification process. We produced the peptide in the periplasm of E. coli using the CASPON™ technology, an affinity fusion technology system that enables high soluble expression of recombinant proteins and cleaves the fusion tag with a circularly permuted human caspase-2. Furthermore, purification of the products is straight forward using an established platform process. Two different case studies for downstream purification are presented, starting with either hydrochloric acid or polyethyleneimine as an extraction aid. After release of affinity-tagged somatostatin-28 out of E. coli's periplasm, several purification steps were performed, delivering a pure peptide solution after the final polishing step. The process was monitored by reversed-phase high-performance liquid chromatography as well as mass spectrometry to determine the yield and correct disulfide bond formation. Monitoring of impurities like host cell proteins, DNA and endotoxins after each downstream unit confirmed effective removal for both purification pathways.
PubMed: 38944221
DOI: 10.1016/j.pep.2024.106537 -
Biological Psychiatry Jun 2024Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and... (Review)
Review
Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and the thoughtful regulation of attention, action and emotion. For example, schizophrenia, depression, long-COVID and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often focused in layer III. The dlPFC has extensive top-down projections: e.g. to the posterior association cortices to regulate attention, and the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state, and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors in most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research, and are summarized in this review. For example, the layer III dlPFC circuits generating working memory-related neuronal firing have unusual neurotransmission, depending on NMDAR and nicotinic-α7R actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A-AR and mGluR3 signaling, but dysregulated by inflammation and/or chronic stress exposure, contributing to spine loss. Treatments that strengthen dlPFC, via pharmacological (the α2A-AR agonist, guanfacine) or rTMS manipulation, provide a rational basis for therapy.
PubMed: 38944141
DOI: 10.1016/j.biopsych.2024.06.016 -
The Journal of Biological Chemistry Jun 2024Shy (side chain hydratase) and Sal (side chain aldolase), are involved in successive reactions in the pathway of bile acid side chain catabolism in Proteobacteria....
Shy (side chain hydratase) and Sal (side chain aldolase), are involved in successive reactions in the pathway of bile acid side chain catabolism in Proteobacteria. Untagged Shy co-purified with His-tagged Sal indicating that the two enzymes form a complex. Shy contains a MaoC and a DUF35 domain. When co-expressed with Sal, the DUF35 domain but not the MaoC domain of Shy was observed to co-purify with Sal, indicating Sal interacts with Shy through its DUF35 domain. The MaoC domain of Shy (Shy) remained catalytically viable and could hydrate cholyl-enoyl-CoA with similar catalytic efficiency as in the Shy-Sal complex. Sal expressed with the DUF35 domain of Shy (Sal-Shy) was similarly competent for the retroaldol cleavage of cholyl-3-OH-CoA. Shy showed a preference for C side chain bile acid substrates, exhibiting low activity towards C side chain substrates. The Shy structure was determined by X-ray crystallography, showing a hot dog fold with a short central helix surrounded by a twisted anti-parallel β-sheet. Modeling and mutagenesis studies suggest that the bile acid substrate occupies the large open cleft formed by the truncated central helix and repositioning of the active site housing. Shy therefore contains two substrate binding sites per homodimer, making it distinct from previously characterized MaoC steroid hydratases that are (pseudo)-heterodimers with one substrate binding site per dimer. The characterization of Shy provides insight into how MaoC family hydratases have adapted to accommodate large polycyclic substrates that can facilitate future engineering of these enzymes to produce novel steroid pharmaceuticals.
PubMed: 38944126
DOI: 10.1016/j.jbc.2024.107509 -
The Journal of Biological Chemistry Jun 2024Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon...
Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver - α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mTORC1, another ErbB3 downstream effector STAT3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mTORC1 and STAT3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.
PubMed: 38944125
DOI: 10.1016/j.jbc.2024.107499