J Allergy Clin Immunol Pract. 2024 Mar 26:S2213-2198(24)00296-4. doi: 10.1016/j.jaip.2024.03.029. Online ahead of print.

ABSTRACT

BACKGROUND: Asthmatic patients with antibody deficiencies (AD) have more severe disease and higher risk of exacerbations. No data exists about the efficacy of biologics in severe asthma (SA) patients with AD. The objective of this study was to evaluate the efficacy of biologics in SA patients with and without AD.

METHODS: A case-control real-life study was conducted including 68 patients divided in two groups: group 1 with SA-AD and group 2 with SA.

RESULTS: Treatment by biologics for 6 months was effective to decrease the number of exacerbations, hospitalizations, and emergency department (ED) visits, to improve the Asthma Control Questionnaire (ACQ) score and proved a systemic corticosteroid sparing effect. Despite benefits, the number of exacerbations, hospitalizations, and ED visits, the mean ACQ score, and the cumulative dose of systemic corticosteroids remain higher in group 1 vs 2, with lower lung function parameters. The rates of responses were inferior in group 1 vs 2 with a decrease by ≥50% of exacerbation rate in 76% vs 97% of patients (p=.006), no hospitalization in 44% vs 91% of patients (p<.001), no ED visit 56% vs 82% of patients (p=.018), significant improvement of ACQ score by ≥0.5 in 68% vs 100% of patients (p<.001), and increase of forced expiratory volume in the first second by >10% in 32% vs 65% of patients (p=.007).

CONCLUSION: Despite evident benefits, SA patients with AD have suboptimal responses to biologics compared to those immunocompetent. A multidisciplinary approach is necessary to optimize the management of these patients in practice.

PMID:38548169 | DOI:10.1016/j.jaip.2024.03.029

Phytomedicine. 2024 Jan 12;128:155360. doi: 10.1016/j.phymed.2024.155360. Online ahead of print.

ABSTRACT

BACKGROUND: Autophagy could sense metabolic conditions and safeguard cells against nutrient deprivation, ultimately supporting the survival of cancer cells. Nobiletin (NOB) is a kind of bioactive component of the traditional Chinese medicine Citri Reticulatae Pericarpium and has been proven to induce GC cell death by reducing de novo fatty acid synthesis in our previous study. Nevertheless, the precise mechanisms by which NOB induces cell death in GC cells still need further elucidation.

OBJECTIVES: To examine the mechanism by which NOB inhibits gastric cancer progression through the regulation of autophagy under the condition of lipid metabolism inhibition.

METHODS/ STUDY DESIGN: Proliferation was detected by the CCK-8 assay. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Electron microscopy and mRFP-GFP-LC3 lentiviral transfection were performed to observe autophagy in vitro. Western blot, plasmid transfection, immunofluorescence staining, and CUT & Tag-qPCR techniques were utilized to explore the mechanisms by which NOB affects GC cells. Molecular docking and molecular dynamics simulations were conducted to predict the binding mode of NOB and SREBP1. CETSA was adopted to verify the predicted of binding model. A patient-derived xenograft (PDX) model was employed to verify the therapeutic efficacy of NOB in vivo.

RESULTS: We conducted functional studies and discovered that NOB inhibited the protective effect of autophagy via the PI3K/Akt/mTOR axis in GC cells. Based on previous research, we found that the overexpression of ACLY abrogated the NOB-induced autophagy-dependent cell death. In silico analysis predicted the formation of a stable complex between NOB and SREBP1. In vitro assays confirmed that NOB treatment increased the thermal stability of SREBP1 at the same temperature conditions. Moreover, CUT&TAG-qPCR analysis revealed that NOB could inhibit SREBP1 binding to the ACLY promoter. In the PDX model, NOB suppressed tumor growth, causing SREBP1 nuclear translocation inhibition, PI3K/Akt/mTOR inactivation, and autophagy-dependent cell death.

CONCLUSION: NOB demonstrated the ability to directly bind to SREBP1, inhibiting its nuclear translocation and binding to the ACLY promoter, thereby inducing autophagy-dependent cell death via PI3K/Akt/mTOR pathway.

PMID:38547624 | DOI:10.1016/j.phymed.2024.155360

Curr Opin Biotechnol. 2024 Mar 27;87:103115. doi: 10.1016/j.copbio.2024.103115. Online ahead of print.

ABSTRACT

With the continuous increment in global population growth, compounded by post-pandemic food security challenges due to labor shortages, effects of climate change, political conflicts, limited land for agriculture, and carbon emissions control, addressing food production in a sustainable manner for future generations is critical. Microorganisms are potential alternative food sources that can help close the gap in food production. For the development of more efficient and yield-enhancing products, it is necessary to have a better understanding on the underlying regulatory molecular pathways of microbial growth. Nevertheless, as microbes are regulated at multiomics scales, current research focusing on single omics (genomics, proteomics, or metabolomics) independently is inadequate for optimizing growth and product output. Here, we discuss digital twin (DT) approaches that integrate systems biology and artificial intelligence in analyzing multiomics datasets to yield a microbial replica model for in silico testing before production. DT models can thus provide a holistic understanding of microbial growth, metabolite biosynthesis mechanisms, as well as identifying crucial production bottlenecks. Our argument, therefore, is to support the development of novel DT models that can potentially revolutionize microorganism-based alternative food production efficiency.

PMID:38547588 | DOI:10.1016/j.copbio.2024.103115

Toxicol Sci. 2024 Mar 28:kfae041. doi: 10.1093/toxsci/kfae041. Online ahead of print.

ABSTRACT

Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing inter-individual difference in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

PMID:38547396 | DOI:10.1093/toxsci/kfae041

PLoS One. 2024 Mar 28;19(3):e0301022. doi: 10.1371/journal.pone.0301022. eCollection 2024.

ABSTRACT

Germinal centers (GCs) are the key histological structures of the adaptive immune system, responsible for the development and selection of B cells producing high-affinity antibodies against antigens. Due to their level of complexity, unexpected malfunctioning may lead to a range of pathologies, including various malignant formations. One promising way to improve the understanding of malignant transformation is to study the underlying gene regulatory networks (GRNs) associated with cell development and differentiation. Evaluation and inference of the GRN structure from gene expression data is a challenging task in systems biology: recent achievements in single-cell (SC) transcriptomics allow the generation of SC gene expression data, which can be used to sharpen the knowledge on GRN structure. In order to understand whether a particular network of three key gene regulators (BCL6, IRF4, BLIMP1), influenced by two external stimuli signals (surface receptors BCR and CD40), is able to describe GC B cell differentiation, we used a stochastic model to fit SC transcriptomic data from a human lymphoid organ dataset. The model is defined mathematically as a piecewise-deterministic Markov process. We showed that after parameter tuning, the model qualitatively recapitulates mRNA distributions corresponding to GC and plasmablast stages of B cell differentiation. Thus, the model can assist in validating the GRN structure and, in the future, could lead to better understanding of the different types of dysfunction of the regulatory mechanisms.

PMID:38547073 | DOI:10.1371/journal.pone.0301022

Elife. 2024 Mar 28;12:RP88623. doi: 10.7554/eLife.88623.

ABSTRACT

We herein introduce voyAGEr, an online graphical interface to explore age-related gene expression alterations in 49 human tissues. voyAGEr offers a visualisation and statistical toolkit for the finding and functional exploration of sex- and tissue-specific transcriptomic changes with age. In its conception, we developed a novel bioinformatics pipeline leveraging RNA sequencing data, from the GTEx project, encompassing more than 900 individuals. voyAGEr reveals transcriptomic signatures of the known asynchronous ageing between tissues, allowing the observation of tissue-specific age periods of major transcriptional changes, associated with alterations in different biological pathways, cellular composition, and disease conditions. Notably, voyAGEr was created to assist researchers with no expertise in bioinformatics, providing a supportive framework for elaborating, testing and refining their hypotheses on the molecular nature of human ageing and its association with pathologies, thereby also aiding in the discovery of novel therapeutic targets. voyAGEr is freely available at https://compbio.imm.medicina.ulisboa.pt/app/voyAGEr.

PMID:38546191 | DOI:10.7554/eLife.88623

Chin Med J (Engl). 2024 Mar 28. doi: 10.1097/CM9.0000000000003073. Online ahead of print.

ABSTRACT

Epitranscriptomics focuses on RNA modifications-mediated post-transcriptional regulation of gene expression. The current decade has witnessed tremendous progress in understanding the landscapes and biological functions of RNA modifications as prompted by potent analytical approaches. The hematopoietic system provides a lifelong supply of blood cells, and gene expression is tightly modulated during the differentiation of hematopoietic stem cells (HSCs). Dysregulation of gene expression during hematopoiesis may lead to severe disorders, including acute myeloid leukemia (AML). Emerging evidence has indicated the involvement of mRNA modification system in normal hematopoiesis and AML pathogenesis, which led to the accelerating development of small-molecule inhibitors targeting N6-methyladenosine (m6A) modification machinery for treatment. Here, we summarize the latest findings and address the state-of-the-art knowledge on the role of m6A and N7-methylguanine (m7G) in both physiological and pathological conditions in the hematopoietic system. Furthermore, we discuss the therapeutic potential and limitations of cancer treatment targeting m6A.

PMID:38545694 | DOI:10.1097/CM9.0000000000003073

Front Immunol. 2024 Mar 13;15:1331480. doi: 10.3389/fimmu.2024.1331480. eCollection 2024.

ABSTRACT

Macrophages are critical regulators of the tumor microenvironment and often present an immuno-suppressive phenotype, supporting tumor growth and immune evasion. Promoting a robust pro-inflammatory macrophage phenotype has emerged as a therapeutic modality that supports tumor clearance, including through synergy with immune checkpoint therapies. Polyglucose nanoparticles (macrins), which possess high macrophage affinity, are useful vehicles for delivering drugs to macrophages, potentially altering their phenotype. Here, we examine the potential of functionalized macrins, synthesized by crosslinking carboxymethyl dextran with L-lysine, as effective carriers of immuno-stimulatory drugs to tumor-associated macrophages (TAMs). Azide groups incorporated during particle synthesis provided a handle for click-coupling of propargyl-modified β-cyclodextrin to macrins under mild conditions. Fluorescence-based competitive binding assays revealed the ability of β-cyclodextrin to non-covalently bind to hydrophobic immuno-stimulatory drug candidates (Keq ~ 103 M-1), enabling drug loading within nanoparticles. Furthermore, transcriptional profiles of macrophages indicated robust pro-inflammatory reprogramming (elevated Nos2 and Il12; suppressed Arg1 and Mrc1 expression levels) for a subset of these immuno-stimulatory agents (UNC2025 and R848). Loading of R848 into the modified macrins improved the drug's effect on primary murine macrophages by three-fold in vitro. Intravital microscopy in IL-12-eYFP reporter mice (24 h post-injection) revealed a two-fold enhancement in mean YFP fluorescence intensity in macrophages targeted with R848-loaded macrins, relative to vehicle controls, validating the desired pro-inflammatory reprogramming of TAMs in vivo by cell-targeted drug delivery. Finally, in an intradermal MC38 tumor model, cyclodextrin-modified macrin NPs loaded with immunostimulatory drugs significantly reduced tumor growth. Therefore, efficient and effective repolarization of tumor-associated macrophages to an M1-like phenotype-via drug-loaded macrins-inhibits tumor growth and may be useful as an adjuvant to existing immune checkpoint therapies.

PMID:38545103 | PMC:PMC10965546 | DOI:10.3389/fimmu.2024.1331480

Adv Funct Mater. 2020 Sep 10;30(37):1910369. doi: 10.1002/adfm.201910369. Epub 2020 Apr 6.

ABSTRACT

Engineered materials are ubiquitous in biomedical applications ranging from systemic drug delivery systems to orthopedic implants, and their actions unfold across multiple time- and length-scales. The efficacy and safety of biologics, nanomaterials, and macroscopic implants are all dictated by the same general principles of pharmacology as apply to small molecule drugs, comprising how the body affects materials (pharmacokinetics, PK) and conversely how materials affect the body (pharmacodynamics, PD). Imaging technologies play an increasingly insightful role in monitoring both of these processes, often simultaneously: translational macroscopic imaging modalities such as MRI and PET/CT offer whole-body quantitation of biodistribution and structural or molecular response, while ex vivo approaches and optical imaging via in vivo (intravital) microscopy reveal behaviors at subcellular resolution. In this review, the authors survey developments in imaging the in situ behavior of systemically and locally administered materials, with a particular focus on using microscopy to understand transport, target engagement, and downstream host responses at a single-cell level. The themes of microenvironmental influence, controlled drug release, on-target molecular action, and immune response, especially as mediated by macrophages and other myeloid cells are examined. Finally, the future directions of how new imaging technologies may propel efficient clinical translation of next-generation therapeutics and medical devices are proposed.

PMID:38545084 | PMC:PMC10972611 | DOI:10.1002/adfm.201910369

Turk J Chem. 2023 Dec 4;48(1):108-115. doi: 10.55730/1300-0527.3643. eCollection 2024.

ABSTRACT

Cancer, a leading global cause of mortality, demands continuous advancements in therapeutic strategies. This study focuses on the design and synthesis of a novel series of purine derivatives, specifically 6-(substituted phenyl piperazine)-8-(4-phenoxyphenyl)-9-cyclopentyl purine derivatives (5-11). The motivation behind this endeavor lies in addressing acquired resistance mechanisms in cancer cells, a significant hurdle in current treatment modalities. The synthesis, starting from 4,6-dichloro-5-nitropyrimidine, involves a multi-step process, resulting in seven new purine derivatives. Biological evaluation against human liver, colon, and breast cancer cells (Huh7, HCT116, and MCF7, respectively) was performed using the SRB assay. Among the synthesized analogs, compounds 5 and 6, exhibited notable cytotoxic activity, surpassing clinically used positive controls 5-Fluorouracil and Fludarabine in terms of efficacy. This research underscores the potential of purine derivatives with a phenyl group at the C-8 position as a scaffold for developing compounds with improved anticancer properties. The findings offer insights for future exploration and development of novel agents in cancer pharmaceutical research.

PMID:38544902 | PMC:PMC10965180 | DOI:10.55730/1300-0527.3643

Front Microbiol. 2024 Mar 13;15:1378989. doi: 10.3389/fmicb.2024.1378989. eCollection 2024.

ABSTRACT

Nature utilizes three distinct pathways to synthesize the essential enzyme cofactor heme. The coproporphyrin III-dependent pathway, predominantly present in Bacillaceae, employs an oxygen-dependent coproporphyrinogen III oxidase (CgoX) that converts coproporphyrinogen III into coproporphyrin III. In this study, we report the bioinformatic-based identification of a gene called ytpQ, encoding a putative oxygen-independent counterpart, which we propose to term CgoN, from Priestia (Bacillus) megaterium. The recombinantly produced, purified, and monomeric YtpQ (CgoN) protein is shown to catalyze the oxygen-independent conversion of coproporphyrinogen III into coproporphyrin III. Minimal non-enzymatic conversion of coproporphyrinogen III was observed under the anaerobic test conditions employed in this study. FAD was identified as a cofactor, and menadione served as an artificial acceptor for the six abstracted electrons, with a KM value of 3.95 μmol/L and a kcat of 0.63 per min for the substrate. The resulting coproporphyrin III, in turn, acts as an effective substrate for the subsequent enzyme of the pathway, the coproporphyrin III ferrochelatase (CpfC). Under aerobic conditions, oxygen directly serves as an electron acceptor, but is replaced by the more efficient action of menadione. An AlphaFold2 model of the enzyme suggests that YtpQ adopts a compact triangular shape consisting of three domains. The N-terminal domain appears to be flexible with respect to the rest of the structure, potentially creating a ligand binding site that opens and closes during the catalytic cycle. A catalytic mechanism similar to the oxygen-independent protoporphyrinogen IX oxidase PgoH1 (HemG), based on the flavin-dependent abstraction of six electrons from coproporphyrinogen III and their potential quinone-dependent transfer to a membrane-localized electron transport chain, is proposed.

PMID:38544863 | PMC:PMC10965808 | DOI:10.3389/fmicb.2024.1378989

Front Microbiol. 2024 Mar 13;15:1393685. doi: 10.3389/fmicb.2024.1393685. eCollection 2024.

NO ABSTRACT

PMID:38544855 | PMC:PMC10965768 | DOI:10.3389/fmicb.2024.1393685

Front Genet. 2024 Mar 13;15:1367731. doi: 10.3389/fgene.2024.1367731. eCollection 2024.

ABSTRACT

Introduction: CpG island (CGI) methylation is one of the key epigenomic mechanisms for gene expression regulation and chromosomal integrity. However, classical CGI prediction methods are neither easy to locate those short and position-sensitive CGIs (CpG islets), nor investigate genetic and expression pattern for CGIs under different CpG position- and interval- sensitive parameters in a genome-wide perspective. Therefore, it is urgent for us to develop such a bioinformatic algorithm that not only can locate CpG islets, but also provide CGI methylation site annotation and functional analysis to investigate the regulatory mechanisms for CGI methylation. Methods: This study develops Human position-defined CGI prediction method to locate CpG islets using high performance computing, and then builds up a novel human genome annotation and analysis method to investigate the connections among CGI, gene expression and methylation. Finally, we integrate these functions into PCGIMA to provide relevant online computing and visualization service. Results: The main results include: (1) Human position-defined CGI prediction method is more efficient to predict position-defined CGIs with multiple consecutive (d) values and locate more potential short CGIs than previous CGI prediction methods. (2) Our annotation and analysis method not only can investigate the connections between position-defined CGI methylation and gene expression specificity from a genome-wide perspective, but also can analysis the potential association of position-defined CGIs with gene functions. (3) PCGIMA (http://www.combio-lezhang.online/pcgima/home.html) provides an easy-to-use analysis and visualization platform for human CGI prediction and methylation. Discussion: This study not only develops Human position-defined CGI prediction method to locate short and position-sensitive CGIs (CpG islets) using high performance computing to construct MR-CpGCluster algorithm, but also a novel human genome annotation and analysis method to investigate the connections among CGI, gene expression and methylation. Finally, we integrate them into PCGIMA for online computing and visualization.

PMID:38544801 | PMC:PMC10965558 | DOI:10.3389/fgene.2024.1367731

iScience. 2024 Mar 1;27(4):109398. doi: 10.1016/j.isci.2024.109398. eCollection 2024 Apr 19.

ABSTRACT

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

PMID:38544573 | PMC:PMC10966194 | DOI:10.1016/j.isci.2024.109398

Sensors (Basel). 2024 Mar 21;24(6):1997. doi: 10.3390/s24061997.

ABSTRACT

We aimed to determine the feasibility, test-retest reliability and long-term stability of a novel method for assessing the force (torque)-velocity (cadence) profile and maximal dynamic force (MDF) during leg-pedaling using a friction-loaded isoinertial cycle ergometer and a high-precision power-meter device. Fifty-two trained male cyclists completed a progressive loading test up to the one-repetition maximum (1RM) on a cycle ergometer. The MDF was defined as the force attained at the cycle performed with the 1RM-load. To examine the test-retest reliability and long-term stability of torque-cadence values, the progressive test was repeated after 72 h and also after 10 weeks of aerobic and strength training. The participants' MDF averaged 13.4 ± 1.3 N·kg-1, which was attained with an average pedal cadence of 21 ± 3 rpm. Participants' highest power output value was attained with a cadence of 110 ± 16 rpm (52 ± 5% MDF). The relationship between the MDF and cadence proved to be very strong (R2 = 0.978) and independent of the cyclists' MDF (p = 0.66). Cadence values derived from this relationship revealed a very high test-retest repeatability (mean SEM = 4 rpm, 3.3%) and long-term stability (SEM = 3 rpm, 2.3%); despite increases in the MDF following the 10-week period. Our findings support the validity, reliability and long-term stability of this method for the assessment of the torque-cadence profile and MDF in cyclists.

PMID:38544265 | DOI:10.3390/s24061997

Viruses. 2024 Mar 18;16(3):465. doi: 10.3390/v16030465.

ABSTRACT

Sturgeon farming is rapidly expanding in Europe, where Italy ranks first in farmed caviar production. A major threat to sturgeon health in captivity is infection with Acipenser European Iridovirus (AcIV-E), a viral disease definitively identified in 2016. Here we present data on the occurrence of AcIV-E in 482 sturgeons (age ≤ 12 months, species of the genus Acipenser and the species Huso huso) collected from sturgeon farms in northern Italy between January 2021 and December 2023. The health status of each specimen was determined by necroscopy and virological assay. Virological analysis was performed on gill samples and real-time PCR specific to the MCP gene of the iridovirus viral capsid. Molecular analysis revealed positivity to the virus in 204 samples (42.68% of the total), while anatomopathological examination of nearly all fish with positive real-time PCR disclosed swollen abdomen, hepatic steatosis, splenomegaly, and increased gill volume. Two challenges to timely diagnosis are the absence of pathognomonic symptoms and the inability to isolate the virus on cell monolayers. Continuous and widespread health monitoring is therefore crucial for disease management and to effectively control spread of the virus.

PMID:38543830 | DOI:10.3390/v16030465

Polymers (Basel). 2024 Mar 13;16(6):796. doi: 10.3390/polym16060796.

ABSTRACT

The non-degradable nature of petroleum-based plastics and the dependence on petroleum-based products in daily life and production are dilemmas of human development today. We hereby developed a plastic waste upcycling process to address these challenges. A multi-stream fraction strategy was developed to process poly (ethylene terephthalate) (PET) plastics into soluble and insoluble fractions. The soluble fraction was used as a sole carbon source for microbial fermentation to produce biodiesel precursor lipids with an appreciable bioconversion yield. The insoluble fraction containing fractionated polymers was used as the asphalt binder modifiers. The downsized PET additive improved the high-temperature performance of the asphalt binder by 1 performance grade (PG) without decreasing the low-temperature PG. Subsequent SEM imaging unveiled alterations in the micromorphology induced by PET incorporation. Further FTIR and 1H NMR analysis highlighted the aromatic groups of PET polymers as a crucial factor influencing performance enhancement. The results demonstrated the multi-stream fraction as a promising approach for repurposing plastic waste to produce biodiesel and modify asphalt. This approach holds the potential to tackle challenges in fuel supply and enhance infrastructure resilience to global warming.

PMID:38543401 | DOI:10.3390/polym16060796

Molecules. 2024 Mar 21;29(6):1398. doi: 10.3390/molecules29061398.

ABSTRACT

Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two separate protocols, which is time-consuming and costly. In this study, we have optimised and validated a simple and unified 3-nitrophenylhydrazine (3-NPH) derivatisation protocol and a 20 min chiral-LC-MS method for the simultaneous quantification of all SCFA and D- and L-lactate in ruminal fluid. This method, which requires no sample pretreatment or purification shows adequate sensitivity (limit of detection (LOD): 0.01 µg/mL), satisfactory accuracy (recovery: 88-103%), and excellent reproducibility (relative standard deviation (RSD) for repeated analyses < 3% for most analytes). The application of this method to a cohort of 24 animals allowed us to reveal a large inter-cow variation in ruminal SCFA and lactate level, the concentration range for each species, the widespread correlation between different SCFA, and the strong correlation between D- and L-lactate.

PMID:38543032 | DOI:10.3390/molecules29061398

Nutrients. 2024 Mar 17;16(6):871. doi: 10.3390/nu16060871.

ABSTRACT

There is currently a growing interest in the use of nutraceuticals as a means of preventing the development of complex diseases. Given the considerable health potential of milk-derived peptides, the aim of this study was to investigate the protective effects of glycomacropeptide (GMP) on metabolic syndrome. Particular emphasis was placed on the potential mechanisms mitigating cardiometabolic disorders in high-fat, high-fructose diet-fed mice in the presence of GMP or Bipro, an isocaloric control. The administration of GMP for 12 weeks reduced obesity, hyperglycemia and hyperinsulinemia caused by a high-fat, high-fructose diet, resulting in a decline in insulin resistance. GMP also lessened systemic inflammation, as indicated by decreased circulating inflammatory cytokines. In the intestinal and hepatic tissues, GMP improved homeostasis by increasing insulin sensitivity and attenuating high-fat, high-fructose-induced inflammation, oxidative stress and endoplasmic reticulum stress. Biochemical and histological analyses revealed improved hepatic steatosis and fatty acid composition in the livers of high-fat, high-fructose diet-fed mice treated with GMP compared to Bipro. A trend toward a decrease in bile acids without any marked changes in intestinal microbiota composition characterized GMP-treated animals compared to those administered Bipro. GMP offers considerable potential for fighting metabolic syndrome-related components and complications given its beneficial effects on risk factors such as inflammation, oxidative stress and endoplasmic reticulum stress without involving the intestinal microbiota.

PMID:38542783 | DOI:10.3390/nu16060871

Int J Mol Sci. 2024 Mar 18;25(6):3427. doi: 10.3390/ijms25063427.

ABSTRACT

Bombyx mori was domesticated from Bombyx mandarina. The long-term domestication of the silkworm has brought about many remarkable changes to its body size and cocoon shell weight. However, the molecular mechanism underlying the improvement in the economic characteristics of this species during domestication remains unclear. In this study, we found that a transposable element (TE)-Bm1-was present in the upstream regulatory region of the Mlx (Max-like protein X) gene in wild silkworms but not in all domesticated silkworms. The absence of Bm1 caused an increase in the promoter activity and mRNA content of Mlx. Mlx and its partner Mondo belong to the bHLHZ transcription factors family and regulate nutrient metabolism. RNAi of Mlx and Mondo decreased the expression and promoter activity of glucose metabolism-related genes (trehalose transport (Tret), phosphofructokinase (PFK), and pyruvate kinase (PK)), lipogenic genes (Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)), and glutamine synthesis gene (Glutamine synthase 2, (GS2)). Furthermore, the transgenic overexpression of Mlx and Mondo in the fat body of silkworms increased the larval body size, cocoon shell weight, and egg number, but the silencing of the two genes resulted in the opposite phenotypes. Our results reveal the molecular mechanism of Mlx selection during domestication and its successful use in the molecular breeding of Bombyx mori.

PMID:38542400 | DOI:10.3390/ijms25063427