Immune Function Research Articles

The immunological landscape of primary biliary cholangitis: Mechanisms and therapeutic prospects.

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease characterized by the progressive destruction of intrahepatic bile ducts, leading to fibrosis, and potentially cirrhosis. PBC has been considered a prototypical autoimmune condition, given the presence of specific autoantibodies and the immune response against well-defined mitochondrial autoantigens. Further evidence supports the interaction of immunogenetic and environmental factors in the aetiology of PBC. An immunological attack on biliary epithelial cells (BECs) with secondary failure of biliary transporters, e.g. the anion exchange protein 2 (AE2), is traditionally considered the primum movens. A recent hypothesis proposes a primary failure of BECs with the downregulation of AE2 secondary to epigenetic mechanisms (miR-506 overexpression) which then triggers the immunological storm. This highlights the secretory defect as culprit and sustaining factor in the pathogenesis of PBC with UDCA helping to restore this protective mechanism by promoting bicarbonate secretion and reducing bile acid toxicity. In this review we aim to provide the most recent evidence on the immunopathogenesis of PBC. We will analyse the immune function of the biliary epithelium, assessing the immunomodulatory functions of the bile acids and the evidence of the immunological roles of the secretory pathways targeted by the current treatments.

IGF2BP1 in Mesenchymal GBM Immune Signalling Regulation via c-Myc

Glioblastoma multiforme (GBM) is a highly aggressive and lethal brain tumor, with poor patient prognosis and median overall survival of only 10 months despite the current Stupp protocol treatment, due to its high aggressiveness and recurrence rate. This study investigated the role of the IGF2BP1 gene in mesenchymal glioblastoma multiforme (GBM), revealing that IGF2BP1 is upregulated in tumor tissues compared to adjacent normal tissues and positively correlates with MYC gene expression and poor patient prognosis. Immune infiltration analysis showed that IGF2BP1 is associated with specific immune cell populations, and GSVA analysis confirmed its positive correlation with the immune functions of most B cells and macrophages. The mechanism of IGF2BP1 regulating c-Myc expression in mesenchymal GBM and its subsequent impact on immune-related signalling pathways, thereby affecting the immune microenvironment of tumors and patient prognosis, provides new targets and ideas for future immunotherapy of mesenchymal GBM.

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

The protein ingredient quality of infant formula influences colonic physiology and microbiota and the serum metabolomic profile in neonatal mini-piglets.

Despite the WHO recommendations in favor of breastfeeding, most infants receive infant formulas (IFs), which are complex matrices involving numerous ingredients and processing steps. Our aim was to understand the impact of the quality of the protein ingredient in IFs on gut microbiota and physiology, blood metabolites and brain gene expression. Three IFs were produced using whey proteins (WPs) from cheese whey (IF-A) or ideal whey (IFs-C and -D) and caseins, either in a micellar form (IFs-A and -C) or partly in a non-micellar form (IF-D). Twenty-four Yucatan minipiglets received one of the IFs from 2- to 21-days of age. The piglets were then euthanized 84min postprandially. Blood, ileal and colonic digesta and tissues, the liver and the hypothalamus were sampled. Gut microbiota composition and activity, the expression of intestinal and brain genes involved in barrier, immune, endocrine, nutrient carrier and neuronal functions and serum metabolite levels were determined. Intestinal paracellular permeability was assessed with an ex vivo Ussing chamber. The data were analyzed using multifactorial and univariate analyses. The colon was the main site to be physiologically affected by the quality of the dairy protein ingredients used in IFs. Colonic paracellular permeability was significantly higher in IF-D-fed piglets than in those receiving IFs-A and -C, in line with the expression of genes encoding tight junction proteins (OCLN, CLDN3 and CLDN4). IF-D up-regulated the colonic expression of genes involved in the immune function (SOCS3, PIGR and TNFα) when compared to IF-A. Although intestinal α- and β-diversities did not significantly differ among IFs, some specific differences were observed, such as the abundances of Campylobacterota phylum and Bacteroides genera and fecal butyrate production, which were increased with IFs-C and -D versus IF-A. The kynurenine pathway was favored in piglets fed IF-D compared to IF-A, based on colonic gene expression and serum metabolites. In addition, levels of some serum metabolites, particularly putrescine, spermidine and spermine, were higher in piglets fed IF-D than IFs-A and -C. Overall, IF-D, which combined ideal WPs and some non-micellar caseins, appeared to differ most from IF-A in terms of its physiological consequences, suggesting that both WP and casein ingredient quality may mediate the physiological properties of IFs, probably through changes to the colonic microbiota composition and activity.

Effects of deoxynivalenol contaminated corn distiller's dried grains with solubles on growth performance, body composition, immunological response, and gastrointestinal health in young pullets

Mycotoxins, particularly deoxynivalenol (DON), are common contaminants in feed ingredients such as corn distiller's dried grains with solubles (DDGS) and pose significant risks to poultry health. This study investigated the effects of feeding naturally DON contaminated DDGS on growth performance, body composition, immunological response, and gastrointestinal health in young pullets. A total of 360, 4-week-old Hy-Line W36 pullets were randomly assigned to diets with increasing levels of naturally DON contaminated DDGS (0, 5, 10, 15, and 20%) over 28 days, resulting in dietary DON concentrations ranging from below the limit of quantification to 15.4 ppm. Diets with DON concentration exceeding 8.9 ppm, corresponding to 15% and 20% DDGS inclusion, resulted in significantly lower body weight gain (BWG) and feed intake (FI) from experimental day 14 to day 28 compared to DON concentration below 5.9 ppm (0, 5 and 10% DDGS groups; P = 0.024 and P = 0.007, respectively). Body composition analysis showed a higher tissue fat percentage in the 20% DDGS group (15.4 ppm DON) by day 28 compared to lower inclusion levels (P = 0.021). Immunologically, a significant increase in the CD4+:CD8+ ratio in spleen was observed in the 20% DDGS group compared to the 0% DDGS group (P = 0.013), whereas both 15 and 20% DDGS inclusion levels significantly increased the ratio in cecal tonsil (P < 0.001). Additionally, interleukin 1β (IL-1β) expression significantly increased in the cecal tonsil by day 28 with 15 and 20% DDGS inclusions (P = 0.002). Gut health was compromised as gut permeability increased linearly with increasing DDGS inclusion (linear, P = 0.043), aligning with significant alterations in the expression of the tight junction protein occludin (OCLN; P = 0.007). Antioxidant responses in the liver showed increased superoxide dismutase (SOD) activity in early exposure (day 13, P = 0.038), followed by decreased SOD activity (P = 0.001) and reduced glutathione (GSH) levels (P < 0.001) by day 28. In conclusion, feeding DON-contaminated DDGS at higher inclusion levels (15% and 20%) with final diet DON concentrations exceeding 8.9 ppm over 28 days adversely affects growth performance, immune function, and gut integrity in young pullets.

Comparison of Serum Vitamin D Status in Critically ill and Non-critically ill Children and its Relationship with Illness Severity and Clinical Outcomes: A Case–Control Study

Abstract Background: The role of vitamin D in immune function is well-established in adults, but remains unclear in children. Objectives: We aimed to determine the prevalence of vitamin D deficiency in critically ill versus non-critically ill children and the correlation between vitamin D level with illness severity and clinical outcomes. Materials and Methods: This was a hospital-based, case–control study involving 35 critically ill and 35 non-critically ill children aged 1 month to 18 years. Serum Vitamin D levels were determined and categorized. Severity of illness of the critically ill group was classified based on calculated modified Sequential Organ Failure Assessment scores, and participants were followed-up until discharge or demise. Results: Median values of vitamin D levels in the critically ill (78.2 ng/mL) and the non-critically ill (60.3 ng/mL) were significantly different (P = 0.003). None of the children in both groups were found to be vitamin D–deficient. There was no significant correlation between vitamin D levels and severity of illness (P = 0.69). Children with overdose, non-toxic levels were less likely to die when compared with those in the optimal range of vitamin D, with odds ratio (95%CI) 0.05 (0.004–0.65). Conclusion: Serum vitamin D deficiency was uncommon in our cohort of critically ill children and was not related to severity of illness, mortality, or length of hospital stay. Although routine vitamin D assessment and supplementation has been proposed to boost the immune system of critically ill adults to help them recover faster, it may not be of added benefit in children.

Effects of on-farm hatching versus hatchery hatching on growth performance, gut development, and intestinal health and function in broiler chickens.

An alternative hatching system known as hatch on-farm (HOF) provides early access to feed compared to hatch in hatchery (HH) system. Early feeding may promote favorable gut development, potentially improving intestinal health and broiler performance. Previous studies have assessed the effects of HOF on chick quality, welfare and performance, its impacts on gut health remain inconclusive. A total of 560 Ross 308 male chicks were reared until d 38, hatched either in a hatchery (n = 280) or on-farm (n = 280), with 14 replicates per system and 20 birds per pen. Production parameters were periodically monitored. Digestive and immune organ characteristics, intestinal permeability and histomorphology were assessed on d 7, 14, and 38. High-throughput qPCR analyzed 79 ileal genes regarding barrier integrity, immune function, nutrient transporters, gut hormones, metabolism, and oxidation. HOF chicks had higher d1 body weights than HH chicks (P < 001), but this advantage disappeared within first week, with no subsequent performance differences. HOF chickens demonstrated increased duodenal villus width on d 7 and 14, and increased ileal crypt depth and submucosal thickness on d 7 (P < 0.05). Relative bursal weight was higher on d 14 (P = 0.018) and tended to be higher on d 38 in HOF chickens (P = 0.094). Intestinal permeability remained unaffected (P > 0.05), while HH chicks showed upregulation of gut barrier genes such as MUC5ac on d 7 and CLDN2 and MUC2 on d 14 (P < 0.05). HH chicks also showed upregulation of nutrient transports including VDR on d 7 and SLC30A1 and SLC5A9 on d 38, and decreased expression of the appetite-suppressing hormone CCK on d 7 (P < 0.05). HOF chicks upregulated immune-related genes, including IL-8 on d 7, IL-6, IFN-γ, AVBD9 on d 14, and NOS2 on d 38 (P < 0.05), and the oxidation gene HIF1A on d 38 (P = 0.039). In conclusion, although the HOF showed only transient growth advantages, it enhanced mucosal morphology and modulated immunity, indicating improved intestinal health.

Hematopoietic stem cell microtransplantation: current situation and challenges.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) stands as a cornerstone in the treatment of hematological malignancies, recognized for its remarkable efficacy. However, the persistent challenge of graft-versus-host disease (GVHD) continues to represent a significant barrier, often being the leading cause of nonrelapse mortality after allo-HSCT. To address this limitation, hematopoietic stem cell microtransplantation (MST) has emerged as a novel therapeutic strategy that synergistically combines chemotherapy, allo-HSCT, and cellular immunotherapy. This innovative approach is designed to retain the patient's immune function, promote the establishment of microchimerism, and achieve a potent graft-versus-tumor (GVT) response, all while significantly minimizing the risk of GVHD. MST has primarily been applied in the treatment of hematological malignancies, where it has demonstrated promising outcomes, including marked improvements in complete remission rates, overall survival rates, and progression-free survival rates. Moreover, MST facilitates hematopoietic recovery, decreases the likelihood of infections, and reduces the incidence of GVHD, thus contributing to an improved quality of life for patients. A deeper and more comprehensive understanding of MST's mechanisms could enhance its clinical utility and integration into standard treatment protocols. This review aims to explore the underlying mechanisms, current clinical applications, and challenges of MST, shedding light on its potential role in advancing the management of hematological malignancies.

Lactobacillus plantarum TWK10 relieves loperamide-induced constipation in rats fed a high-fat diet via modulating enteric neurotransmitters, short-chain fatty acids and gut microbiota.

Obesity and constipation can alter the intestinal microbiota composition, affecting intestinal barrier integrity, immune function, and metabolic processes. Numerous studies have suggested that Lactobacillus and Bifidobacterium could increase short-chain fatty acid (SCFA) production, thus improving the intestinal microbiota composition, mitigating obesity, and protecting the gastrointestinal tract. Therefore, in this study, we aimed to investigate the impact of Lactobacillus plantarum TWK10 (TWK10) on gut dysbiosis, obesity, and constipation induced by a high-fat diet and loperamide. Over a 5-week experimental period, rats were fed a high-fat diet and subsequently induced with gut dysbiosis and constipation using loperamide. Concurrently, rats were administered different doses of TWK10 or TWK10-fermented soy milk. Following administration of TWK10 or its fermented soy milk, the expression of adipocyte transcription factors such as PPARγ, C/EBPα, and C/EBPβ proteins and adipocyte size were significantly downregulated (p < 0.05). Regarding intestinal motility, compared to the high-fat diet-induced obesity and loperamide-induced constipation group (L), rats receiving TWK10 or its fermented soy milk exhibited regulation of gastrointestinal hormone levels such as gastrin (GT), somatostatin (Sst), calcitonin gene-related peptide (CGRP), and acetylcholinesterase (Ache) in serum. Additionally, there was a notable increase in the intestinal transit ratio, particularly in the 1X TWK10 group, in which it increased by 10.29% (p < 0.05). Furthermore, the consumption of TWK10 or its fermented soy milk significantly increased the number of goblet cells, as well as the thickness of the muscle and mucosal layers in the colon (p < 0.05). Analysis of SCFA content in fecal samples revealed a significant increase in SCFA concentrations, particularly acetic acid, following administration of both TWK10 and its fermented soy milk. Finally, TWK10 was found to modulate the composition of the intestinal microbiota and increase microbial diversity. In conclusion, TWK10 and its fermented soy milk effectively alleviated loperamide-induced constipation in rats fed a high-fat diet. These findings suggest that TWK10 and its fermented soy milk may potentially be functional foods for promoting intestinal health.

Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment.

We present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, n = 17), muscle-invasive bladder cancer (MIBC, n = 51), and neoadjuvant-treated MIBC (n = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and analyzed using data-independent acquisition, yielding >8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell-cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid/DNA metabolism. Treatment-naïve MIBC presents three proteomic subgroups with resemblance to the basal-squamous, stroma-rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune-depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP-14. Genomic panel sequencing yielded the prototypical profile of prevalent FGRF3 alterations in NMIBC and TP53 alterations in MIBC. Tumor-stroma interactions of MIBC were investigated by proteomic analysis of patient-derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor-induced stromal proteome phenotypes. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A 3D-printed multi-compartment organ-on-chip platform with a tubing-free pump models communication with the lymph node.

Multi-organ-on-chip systems (MOOCs) have the potential to mimic communication between organ systems and reveal mechanisms of health and disease. However, many existing MOOCs are challenging for non-experts to implement due to complex tubing, electronics, or pump mechanisms. In addition, few MOOCs have incorporated immune organs such as the lymph node (LN), limiting their applicability to model critical events such as vaccination. Here we developed a 3D-printed, user-friendly device and companion tubing-free impeller pump with the capacity to co-culture two or more tissue samples, including a LN, under a recirculating common media. Native tissue structure and immune function were incorporated by maintaining slices of murine LN tissue ex vivo in 3D-printed mesh supports for at least 24 h. In a two-compartment model of a LN and an upstream injection site in mock tissue, vaccination of the multi-compartment chip was similar to in vivo vaccination in terms of locations of antigen accumulation and acute changes in activation markers and gene expression in the LN. We anticipate that in the future, this flexible platform will enable models of multi-organ immune responses throughout the body.

Galactose oxidase oxidation and glycosidase digestion for glycoRNA analysis.

Ribonucleic acid (RNA), essential for protein production and immune function, undergoes glycosylation, a process that attaches glycans to RNA, generating unique glycoRNAs. These glycan-coated RNA molecules regulate immune responses and may be related to immune disorders. However, studying them is challenging due to RNA's fragility. Therefore, a robust method for identifying glycoRNA is important. To address this, we optimized parameters for RNA stability, oxidation, and digestion, thereby enriching and identifying glycoRNAs. This breakthrough paves the way for exploring their potential interactions with immune receptors and tumor suppression. Our approach involved investigating factors such as preservation reagent, enzyme buffer, digestion temperature, oxidant, glycosidase, and incubation time. We successfully optimized digestion conditions, achieving efficient cleavage of N-linked glycoRNAs at room temperature using 25 mM ammonium bicarbonate, demonstrating the effectiveness of this method. Additionally, RNA preservation in RNAlater at -80 °C allows controlled release of glycoRNAs within hours. While sequential digestion of different glycoRNA types is possible, significant degradation occurs after the first glycosidase step. Therefore, we recommend separate harvesting for each glycoRNA type. We also established RNA-seq analysis for identifying various glycoRNA types, including snoRNAs and tRNAs. The optimized SPCgRNA method paves the way for further research on N-glycosylation in health and disease.

Tissue Determinants of Antiviral Immunity in the Liver.

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.

Urbanization enhances body condition, but not innate immune defences, in a common waterbird

There is a growing body of evidence that urbanization can affect body condition and immune function in wild birds, although these effects may be complex and taxa-specific. Here, we assessed the effects of urbanization on body condition (size-corrected body mass and haemoglobin concentration) and innate immune defences (haemolysis–haemagglutination assay, haptoglobin concentration and bacterial killing assay) in 136 Eurasian coots ( Fulica atra ) from three urban and three non-urban populations across Poland. We also quantified the heterophil to lymphocyte ratio to control for the potential effect of physiological stress on immune defences. We found that urban coots showed significantly better condition than non-urban ones. At the same time, we found no relationship between any immune defence and urbanization or condition. Thus, our study offers no support for condition-dependent immune function. Our analyses also revealed significant differences between male and female coots in both condition and immune defences; however, we found no evidence for sex-specific responses to urbanization. In conclusion, our study provides correlative evidence that urban habitat enhances condition, but not immune defences in the Eurasian coot.

Enhancing Broiler Growth and Carcass Quality: Impact of Diets Enriched with Moringa oleifera Leaf Powder Conjugated with Zinc Nanoparticles

This study evaluated the effects of Moringa oleifera leaf powder extract stabilized with zinc nanoparticles (ZnNPs-MLPE) as a natural growth promoter in broiler diets. Randomly assigned 264 one-day-old Ross 308 chicks to four different feeding treatments, with each group being subdivided into six replicates, each comprising 11 unsexed chicks. The control group was fed a basic diet without additives, while the experimental groups were supplemented with 1.0, 2.0, or 3.0 cm³ of ZnNPs-MLPE/L of diet. The findings demonstrated that 2.0 and 3.0 cm³/L ZnNPs-MLPE supplementation significantly enhanced live body weight (LBW) and weight gain (BWG). Feed intake (FI) and feed conversion ratio (FCR) did not show significant differences between the treated groups and the control, indicating that the additive did not negatively affect feed efficiency. However, an increase in abdominal fat was noted in the ZnNPs-MLPE treatments relative to the control. Blood analysis revealed that the ZnNPs-MLPE groups had significantly lower levels of "total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and alanine transaminase (ALT) compared to the control group. In contrast, total protein (TP), albumin, and the albumin/globulin (A/G) ratio" were higher in the ZnNPs-MLPE groups. Immunoglobulins IgY and IgM, as well as superoxide dismutase (SOD) levels, were elevated. Malondialdehyde (MDA) levels were reduced, indicating improved antioxidant capacity and immune function in the ZnNPs-MLPE-treated groups. In conclusion, supplementation with ZnNPs-MLPE at 2.0 and 3.0 cm³/L positively impacted broiler growth efficiency, antioxidant capacity, and immunological functionality. These findings support the potential of ZnNPs-MLPE as an effective natural growth enhancer for producing healthier poultry products.

Transcriptomics Reveals Crowding Stress Inhibit the Immune Defense of The Head kidney of The Pearl Gentian Grouper Juvenile through NF-κB Signal Pathway

Crowding stress is a significant welfare factor affecting aquatic animals in recirculating aquaculture systems. Little is known regarding the influence of prolonged crowding stress on the immunity of juvenile pearl gentian groupers. However, research exploring the potential mechanisms through which crowding stress affects fish immune function is limited. Therefore, this study aims to investigate the effect of crowding stress on the immune stress of the pearl gentian grouper juvenile (♀Epinephelus fuscoguttatus × ♂ Epinephelus lanceolatus) under prolonged conditions. We focused on the pearl gentian grouper juvenile and selected low- and high-density groups as the experimental breeding densities. Research shows that crowding stress increases the activities of alkaline acid plum and acid phosphatase, reduces the activities of lysozyme and immunoglobulin M content. RNA sequencing and comparative transcriptomic analyses were employed to explore changes in the gene expression of juvenile pearl gentian groupers subjected to crowding stress. Differential gene expression analyses between the low- and high-density groups identified 5777 unigenes that were differentially expressed following crowding stress, with 3216 and 2561 upregulated and downregulated, respectively. In the GO and KEGG enrichment analyses, many of the enriched signaling pathways related to genes were associated with immunity and oxidative stress. In addition, the combined analyses of enzyme activity and transcriptomics indicated that crowding stress suppressed the immune function of juvenile pearl gentian groupers, reducing their immune ability. Overall, these findings offer new insights into the molecular mechanisms underlying crowding stress tolerance in juvenile pearl gentian grouper, suggesting that the NF-κB pathway plays a crucial role in the immune response of the head kidney of the pearl gentian grouper to long-term crowding stress.

Impact of Lysine to Methionine Ratios on Antioxidant Capacity and Immune Function in the Rumen of Tibetan Sheep: An RNA-Seq Analysis.

With global protein prices on the rise, lowering protein levels in animal feed, together with balancing diet composition and reducing nitrogen emissions, can both reduce the environmental impact of agriculture and save on feed costs. However, the formulation of an ideal amino acid (AA) composition is crucial for better protein utilization by livestock. This study aimed to investigate the effects of different lysine to methionine ratios on the antioxidant capacity and immune function of the rumen in Tibetan sheep. Ninety male Tibetan sheep, weaned at 2 months of age, were randomly divided into three groups (1:1, 2:1 and 3:1 lysine ratios) and subjected to a 100-day feeding trial. RNA sequencing (RNA-seq) was utilized to analyse the impact of different AA ratios on gene expression in rumen tissue, whereas the levels of antioxidant enzymes (total antioxidant capacity [T-AOC], superoxide dismutase [SOD], glutathione peroxidase [GSH-Px] and catalase [CAT]) and immunoglobulins (immunoglobulin A [IgA], immunoglobulin G [IgG] and immunoglobulin M [IgM]) were evaluated. The results indicated that the 1:1 group significantly upregulated the expression of PTGS2, PLA2G12A and PLA2G4 genes, enhancing antioxidant enzyme activity, reducing free radical production and modulating systemic immune responses. COL16A1 and KCNK5 were highly expressed in the protein digestion and absorption pathway, maintaining the structural integrity and function of the rumen epithelium. BMP4 and TGFBR2 were significantly enriched in the cytokine-cytokine receptor interaction pathway and positively correlated with CAT and T-AOC. ITGA8 was upregulated in the 1:1 group, participating in the regulation of various cellular signalling pathways. ATP2B1 was enriched in the cyclic guanosine monophosphate (cGMP)- protein kinase G (PKG) signalling and mineral absorption pathways, primarily influencing oxidative stress and immune responses by regulating intracellular calcium ion concentration. This study demonstrates that a 1:1 lysine to methionine ratio is most beneficial for enhancing the antioxidant capacity and immune function of the rumen in Tibetan sheep.

Sarcopenia and immune-mediated inflammatory diseases: Evaluating causality and exploring therapeutic targets for sarcopenia through Mendelian randomization.

An increasing body of evidence has revealed the association between immune-mediated inflammatory diseases (IMIDs) and sarcopenia. However, a genetically direct causality between IMIDs and sarcopenia remains elusive. To investigate the relationship between IMIDs and sarcopenia-related traits and identify potential therapeutic targets, a Mendelian randomization (MR) was performed. We collected publicly available genome-wide association studies (GWAS) data for seven common IMIDs, including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PSO), ankylosing spondylitis (AS), and rheumatoid arthritis (RA). Additionally, summary-level GWAS data for sarcopenia-related traits, including appendicular lean mass (ALM), left-hand grip strength, and right-hand grip strength were collected. To search for therapeutic targets, we used two types of genetic instruments to proxy the exposure of druggable genes, including genetic variants within or nearby drug targets and expression quantitative trait loci (eQTLs) of drug targets. Two-sample MR and summary-data-based MR (SMR) were used to calculate effect estimates, and sensitivity analyses were implemented for robustness. Drug tractability, gene enrichment analysis, and protein-protein interaction (PPI) analysis were used to validate the biological and clinical significance of the selected drug targets. The two-sample MR analysis indicated the existence of casual associations between IMIDs and sarcopenia-related traits in the overall and sex-stratified populations. In particular, PSO had causal effects on decreased ALM, which showed significance in all six MR analysis tests with directional consistency in the overall population. Grounded in this robust association, HLA-DRB5, HLA-DRB1, and AGER were identified as potential therapeutic targets for ALM decline by drug target MR and further confirmed by SMR analysis. These genes were associated with therapeutic agents currently undergoing evaluations in clinical trials. Gene enrichment and PPI analysis indicated a strong association of these genes with immune functions. This MR study contributes novel genetic evidence supporting the causal link between IMIDs and sarcopenia, with a particular emphasis on the association between PSO and decreased ALM. Additionally, AGER, HLA-DRB1, and HLA-DRB5 emerge as potential therapeutic targets for ALM decline.

Trimethylamine N-oxide in cardiovascular disease: Pathophysiology and the potential role of statins.

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7% from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.

Gene expression profiles based on maternal plasma cfDNA nucleosome footprints indicate fetal development and maternal immunity changes during pregnancy progress.

Pregnancy significantly alters the maternal immune system, affecting fetal development. The collection of tissues from the human placenta and fetus is not ethically or practically feasible at various gestational stages, thus limiting the study of gene expression in the fetus and placenta. Recent studies have shown that plasma cell-free DNA (cfDNA) nucleosome patterns can predict gene expression in the source tissue, offering insights into an individual's health status. This study aimed to identify pregnancy-related gene expression changes across gestational periods using cfDNA nucleosome distribution to understand fetal development and maternal immune changes. Plasma samples were collected from 150 healthy pregnant women in different trimesters (early, mid, and late) and 32 healthy nonpregnant women. The correlation between gene expression and physiological changes during pregnancy was evaluated by inferring differential expression profiles around the transcription start site (TSS) using cfDNA nucleosome distribution patterns obtained through whole-genome sequencing. We utilized Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to annotate differentially expressed genes with the mother and fetus. We identified gene expression changes that support the regulation of fetal development and immune system function during pregnancy. Differential coverage genes were mainly enriched in pathways related to transcription and translation, organic compound metabolism, and immune regulation. In addition, differentially expressed genes with significant temporal trends were identified. Among them, the upregulated differential genes were mainly related to development, whereas those with downregulated trends were mainly related to the immune system response. This indicates that differential changes of the placenta and maternal are significantly correlated with the pregnancy status. This study demonstrated the differential gene expression represented by the characteristic distribution of cfDNA nucleosome in maternal peripheral blood can effectively capture significant changes in maternal immunity and fetal development throughout pregnancy stages. It may help identify abnormal gene expression patterns associated with complications in pregnancy and childbirth, enhancing the quality of life and safety for both mother and fetus.