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Aberration in leptin expression is one of the most frequent features in the onset and progression of obesity, but the underlying mechanisms are still unclear and need to be clarified. This study investigated the effects of the absence of gut microbiota on body weight and the expression and promoter methylation of the leptin. Male C57 BL/6 J germ-free (GF) and conventional (CV) mice (aged 4–5 weeks) were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for 16 weeks. Six to eight mice from each group, at 15 weeks, were administered exogenous leptin for 7 d. Leptin expression and body weight gain in GF mice were increased by NFD with more CpG sites hypermethylated at the leptin promoter, whereas there was no change with HFD, compared with CV mice. Adipose or hepatic expression of genes associated with fat synthesis (Acc1, Fas and Srebp-1c), hydrolysis and oxidation (Atgl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was lower, and hypothalamus expression of Pomc and Socs3 was higher in GF mice than levels in CV mice, particularly with NFD feeding. Exogenous leptin reduced body weight in both types of mice, with a greater effect on CV mice with NFD. Adipose Lep-R expression was up-regulated, and hepatic Fas and hypothalamic Socs3 were down-regulated in both types of mice. Expression of fat hydrolysis and oxidative genes (Atgl, Hsl, Cpt1a, Cpt1c, Ppar-α and Pgc-1α) was up-regulated in CV mice. Therefore, the effects of gut microbiota on the leptin expression and body weight were affected by dietary fat intake.
Inflammatory cascades are a critical component of the immune response to infection or tissue damage, involving an array of signals, including water-soluble metabolites, lipid mediators and several classes of proteins. Early investigation of these signaling pathways focused largely on immune cells and acute disease models. However, more recent findings have highlighted critical roles of both immune cells and inflammatory mediators on tissue remodeling and metabolic homeostasis in healthy animals. In dairy cattle, inflammatory signals in various tissues and in circulation change rapidly and dramatically, starting just prior to and at the onset of lactation. Furthermore, several observations in healthy cows point to homeostatic control of inflammatory tone, which we define as a regulatory process to balance immune tolerance with activation to keep downstream effects under control. Recent evidence suggests that peripartum inflammatory changes influence whole-body nutrient flux of dairy cows over the course of days and months. Inflammatory mediators can suppress appetite, even at levels that do not induce acute responses (e.g. fever), thereby decreasing nutrient availability. On the other hand, inhibition of inflammatory signaling with non-steroidal anti-inflammatory drug (NSAID) treatment suppresses hepatic gluconeogenesis, leading to hypoglycemia in some cases. Over the long term, though, peripartum NSAID treatment substantially increases peak and whole-lactation milk synthesis by multiparous cows. Inflammatory regulation of nutrient flux may provide a homeorhetic mechanism to aid cows in adapting to rapid changes in metabolic demand at the onset of lactation, but excessive systemic inflammation has negative effects on metabolic homeostasis through inhibition of appetite and promotion of immune cell activity. Thus, in this review, we provide perspectives on the overlapping regulation of immune responses and metabolism by inflammatory mediators, which may provide a mechanistic underpinning for links between infectious and metabolic diseases in transition dairy cows. Moreover, we point to novel approaches to the management of this challenging phase of the production cycle.
A reduced protein intake causes a decrease in insulin-like growth factor 1 (IGF1) concentrations and modulates Ca homoeostasis in young goats. IGF1 is synthesised by the liver in response to stimulation by growth hormone (GH). Due to rumino-hepatic circulation of urea, ruminants are suitable for investigating the effects of protein reduction despite sufficient energy intake. The present study aimed to investigate the impact of a protein-reduced diet on the expression of components of the somatotropic axis. Male young goats were divided into two feeding groups receiving either a control diet (20 % crude protein (CP)) or a reduced-protein diet (9 % CP). Blood concentrations of IGF1 and GH were measured, and a 24-h GH secretion profile was compiled. Moreover, ionised Ca and insulin concentrations as well as mRNA and protein expression levels of hepatic proteins involved in GH signalling were quantified. Due to the protein-reduced diet, concentrations of ionised Ca, insulin and IGF1 decreased significantly, whereas GH concentrations remained unchanged. Expression levels of the hepatic GH receptor (GHR) decreased during protein reduction. GHR expression was down-regulated due to diminished insulin concentrations as both parameters were positively correlated. Insulin itself might be reduced due to reduced blood Ca levels that are involved in insulin release. The protein-reduced diet had an impact on the expression of components of the somatotropic axis as a disruption of the GH–IGF1 axis brought about by diminished GHR expression was shown in response to a protein-reduced diet.
Fermented feeds are being considered as practical alternatives to antimicrobial growth promoters (AGP) supplemented in nursery pig diets. This study aimed to investigate health-promoting effects of fermented barley in weaned pigs challenged with Escherichia coli K88 +. A total of 37 piglets were weaned at 21 ± 1 day of age (6.41 ± 0.47 kg of BW) and assigned to either of the following five treatment groups: (1) unchallenged control (UCC; n = 7), (2) challenged control (CC; n = 7), (3) AGP (CC + 0.1% AGP; n = 7), (4) Ferm1 (challenged and fed homofermentative Lactobacillus plantarum (Homo)-fermented barley; n = 8) and (5) Ferm2 (challenged and fed heterofermentative L. buchneri (Hetero)-fermented barley; n = 8). The control diet included unfermented barley. Barley was fermented with either Homo or Hetero for 90 days under anaerobic conditions. On day 10, all pigs except those in UCC group were orally inoculated with E. coli K88 + (6 × 109 colony forming units/ml). The pre-planned orthogonal test was performed to compare (1) UCC and CC, (2) CC and AGP, (3) CC and Ferm1 + Ferm2, as well as (4) Ferm1 and Ferm2. Challenged control pigs showed shorter (P < 0.05) villus height (VH) in the duodenum and deeper (P < 0.05) crypt depth (CD) in the jejunum than UCC pigs. The AGP group had higher (P < 0.05) VH and lower (P < 0.05) IL-6 gene expression in the jejunum compared with CC group. Compared to CC, Ferm1 and Ferm2 had decreased (P < 0.05) CD in the duodenum, IL-6 gene expression in the jejunum and rectal temperature at 24 h post-challenge. Pigs fed fermented barley diets showed greater (P < 0.05) faecal abundance of Clostridium Cluster IV and Lactobacilli than those fed UCC diet. Ferm2-fed pigs showed lower (P < 0.05) concentrations of band cells, eosinophils and lymphocytes at 6, 24 and 48 h after challenge, respectively, and lower (P < 0.05) faecal abundance of Enterobacteriaceae 24 h after challenge than the Ferm1-fed pigs. In conclusion, the substitution of unfermented barley with fermented barley in a nursery diet showed similar results as those shown by AGP supplementation in terms of enhancing the intestinal morphology and modulating faecal microbiota composition, as well as down-regulating the pro-inflammatory cytokines; therefore, fermented barley can be a possible nutritional strategy for managing nursery pigs fed diets without in-feed AGP.
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of ‘developmental origins of health and disease’. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
Recent studies have strongly indicated the hepatoprotective effect of curcumin; however, the precise mechanisms are not well understood. This study aimed to determine the protective effect of curcumin on hepatic damage and hepatic insulin resistance in biliary duct ligated (BDL) fibrotic rat model. To accomplish this, male Wistar rats were divided into four groups (eight for each): sham group, BDL group, sham+Cur group and BDL+Cur group. The last two groups received curcumin at a dose of 100 mg/kg daily for 4 weeks. The mRNA/protein expression levels of Ras-related C3 botulinum toxin substrate 1 (Rac1), Rac1-GTP, dinucleotide phosphate oxidase 1 (NOX1), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signalling 3 (SOCS3), insulin receptor substrate 1 (IRS1), extracellular signal-regulated kinase 1 (ERK1), specific protein 1 (Sp1) and hypoxia-inducible factor-1α (HIF-1α) were measured by real-time PCR and Western blotting, respectively. Fasting blood glucose, insulin and Leptin levels were determined and homoeostasis model assessment-estimated insulin resistance, as an index of insulin resistance, was calculated. Curcumin significantly attenuated liver injury and fibrosis, including amelioration of liver histological changes, reduction of hepatic enzymes, as well as decreased expression of liver fibrogenesis-associated variables, including Rac1, Rac1-GTP, NOX1, ERK1, HIF-1α and Sp1. Curcumin also attenuated leptin level and insulin resistance, which had increased in BDL rats (P<0·05). Furthermore, compared with the BDL group, we observed an increase in IRS1 and a decrease in SOCS3 and STAT3 expression in the curcumin-treated BDL group (P<0·05), indicating return of these parameters towards normalcy. In conclusion, Curcumin showed hepatoprotective activity against BDL-induced liver injury and hepatic insulin resistance by influencing the expression of some genes/proteins involved in these processes, and the results suggest that it can be used as a therapeutic option.
The objective of the current experiment was to determine the effects of high-concentration phytase (5000 FTU/kg) feeding to diverse lines of chickens fed phosphorus (P) adequate maize–soybean meal diets (4.5 g/kg non-phytate P) on the performance and intestinal immune function. Performance was measured for outbred broiler (Ross 308) and inbred Fayoumi lines over 0–21 days, and duodenum and ileum were harvested for the determination of mucin-2, interleukin (IL)-1β and IgA mRNA by quantitative reverse transcription polymerase chain reaction. Over the 0–7-day period, there was a significant line × diet interaction, as high phytase supplementation increased broiler average daily gain (ADG), but had no effect on Fayoumi ADG. Treatment of diets with phytase increased expression of the mucin-2 gene in the duodenum mucosa. There were significant interactions between line and age, and line, diet and age on duodenal expression of the IL-1β gene as phytase supplementation of the broiler line reduced IL-1β in comparison to control fed broilers without change in the Fayoumi line. Overall, the addition of a high concentration of phytase to broilers fed adequate concentrations of non-phytate P resulted in improved growth performance early with a reduction in this effect over time. Mucosal mucin-2 expression was increased with high-concentration phytase feeding across both lines, but IL-1β mRNA expression was reduced in the duodenum of broilers fed high concentrations of phytase, suggesting that the increased performance noted might be related to decreased inflammation.
The mammalian target of rapamycin (mTOR) has been shown to be involved in lipopolysaccharide (LPS)-induced immune responses in many mammal cells. Here, we suggest that the mTOR pathway is involved in the intestinal inflammatory responses evoked by LPS treatment in chicken embryos. The intestinal tissue from Specific pathogen free chick embryos was cultured in the presence of LPS for 2 h. Secretory immunoglobulin A (sIgA) concentrations, messenger RNA (mRNA) expression of cytokines, and protein levels of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), mTOR and p70 ribosomal S6 kinase (p70S6K) were determined. The results showed that LPS treatment increased sIgA concentrations in a dose-dependent manner. The mRNA levels of interleukine (IL)-6, IL-8, IL-10, tumor necrosis factor-α and Toll-like receptor (TLR) 4 were upregulated by LPS treatment (P<0.05). Lipopolysaccharide increased the phosphorylation of Jun N-terminal kinase (JNK), p38 MAPK and NF-κB (P<0.05) while decreasing the phosphorylation level of mTOR (P<0.05). Supplementation of leucine at doses of 10, 20 and 40 mM dose-dependently decreased sIgA production. Leucine supplementation at 40 mM restored the phosphorylation level of mTOR and p70S6K while suppressing the phosphorylation levels of NF-κB (P<0.05) and partially down-regulating the phosphorylation of p38 MAPK and JNK. The transcription of IL-6 was significantly decreased by leucine supplementation. These results suggested that leucine could alleviate LPS-induced inflammatory responses by down-regulating NF-κB signaling pathway and evoking mTOR/p70S6K signaling pathway, which may involve in the regulation of the intestinal immune system in chicken embryos.
We studied the mammary immune response to different mammary pathogenic Escherichia coli (MPEC) strains in cows, hypothesising that the dynamics of response would differ. E. coli is a major aetiologic agent of acute clinical bovine mastitis of various degrees of severity with specific strains being associated with persistent infections. We compared challenge with three distinct pathogenic MPEC strains (VL2874, VL2732 and P4), isolated from different forms of mastitis (per-acute, persistent and acute, respectively). A secondary objective was to verify the lack of mammary pathogenicity of an environmental isolate (K71) that is used for comparison against MPEC in genomic and phenotypic studies. Twelve cows were challenged by intra-mammary infusion with one of the strains. Cellular and chemokine responses and bacterial culture follow-up were performed for 35 d. All cows challenged by any of the MPEC strains developed clinical mastitis. Differences were found in the intensity and duration of response, in somatic cell count, secreted cytokines (TNF-α, IL-6 and IL-17) and levels of milk leucocyte membrane Toll-like receptor 4 (TLR4). A sharp decrease of TLR4 on leucocytes was observed concomitantly to peak bacterial counts in milk. Intra-mammary infusion of strain K71 did not elicit inflammation and bacteria were not recovered from milk. Results suggest some differences in the mammary immune response to distinct MPEC strains that could be correlated to their previously observed pathogenic traits. This is also the first report of an E. coli strain that is non-pathogenic to the bovine mammary gland.
Accumulating evidence indicate a role for the immune system particularly inflammation and autoimmunity in the aetiology of major psychiatric disorders such as depression and schizophrenia. In this paper, we discuss some of the key advances in immunopsychiatry in order to highlight to psychiatrists and other health professionals how an increased understanding of this field might enhance our knowledge of illness mechanism and approaches to treatment. We present a brief overview of clinical research that link inflammation and autoimmunity with depression and psychosis, including potential role of inflammation in treatment response, current evidence for the effectiveness of immune-modulating treatment for depression and psychosis, and possible role of inflammation in common physical comorbidities for these disorders such as coronary heart disease and diabetes mellitus. Gaining a better understanding of the role of immune system could be paradigm changing for psychiatry. We need collaborations between clinicians and scientists to deliver high-quality translational research in order to fully realise the clinical potential of this exciting and rapidly expanding field.
Chimeric antigen receptor T cells are used in the treatment of B-cell leukemias. Common chimeric antigen receptor T-cell toxicities can range from mild flu-like symptoms, such as fever and myalgia, to a more striking neuropsychiatric toxicity that can present as discrete neurological symptoms and delirium. We report here two cases of chimeric antigen receptor T-cell neuropsychiatric toxicity, one who presented as a mild delirium and aphasia that resolved without intervention, and one who presented with delirium, seizures, and respiratory insufficiency requiring intensive treatment. The current literature on the treatment and proposed mechanisms of this clinically challenging chimeric antigen receptor T-cell complication is also presented.
This study was conducted to determine the optimal space allowance for maximizing the growth performance of pigs at each of the following five growth stages (based on BW ranges): stage 1, 11 to 25 kg BW; stage 2, 25 to 45 kg BW; stage 3, 45 to 65 kg BW; stage 4, 65 to 85 kg BW; and stage 5, 85 to 110 kg BW. A total of 1590 crossbred (Landrace×Yorkshire×Duroc) pigs were assigned to one of four treatments at each growth stage, with three replicates each. Pen areas at each growth stage were 6, 11, 16, 19.5 and 20 m2 for stages 1 to 5, respectively. Space allowances for the four treatments at each growth stage were modified by varying the number of pigs per pen (22, 25, 28 and 31 pigs in T1, T2, T3 and T4, respectively). Blood samples were collected on the final day of each growth stage. The average daily gain (ADG) decreased significantly with decreased space allowances at all growth stages, except at stage 2. Average daily feed intake (ADFI) was not significantly affected by space allowances at stages 1 to 4; however, at stage 5, there was a linear effect of space allowance on ADFI. Thus, the feed conversion ratio showed results similar to those for ADG. Serum cortisol concentrations, indicating the level of stress response, increased as space allowances decreased. The highest serum cortisol concentrations were observed in T3 at stages 2 to 5. Serum tumor necrosis factor-α levels were significantly higher in association with a small space allowance than with at large space allowance at stages 2, 4 and 5. Serum interleukin-1β levels also increased in a significant linear manner at every growth stage in pigs reared at a low space allowance, except at stage 4 (P=0.068). This study found that limited space allowance decreases the growth performance of pigs and induces stress and inflammatory responses. We confirmed that no significant effect of space allowance on growth performance and serum cortisol concentrations are observed between T1 and T2 across all growth stages. We suggest that the optimal space allowances for pigs according to their BW are as follows: 0.24, 0.44, 0.64, 0.78 and 0.80 m2/pig for BWs of 11 to 25, 25 to 45, 45 to 65, 65 to 85 and 85 to 115 kg, respectively.
Pro-inflammatory cytokines are critical in mechanisms of muscle atrophy. In addition, asparagine (Asn) is necessary for protein synthesis in mammalian cells. We hypothesised that Asn could attenuate lipopolysaccharide (LPS)-induced muscle atrophy in a piglet model. Piglets were allotted to four treatments (non-challenged control, LPS-challenged control, LPS+0·5 % Asn and LPS+1·0 % Asn). On day 21, the piglets were injected with LPS or saline. At 4 h post injection, piglet blood and muscle samples were collected. Asn increased protein and RNA content in muscles, and decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). However, Asn had no effect on the protein abundance of MAFbx and MuRF1. In addition, Asn decreased muscle AMP-activated protein kinase (AMPK) α phosphorylation, but increased muscle protein kinase B (Akt) and Forkhead Box O (FOXO) 1 phosphorylation. Moreover, Asn decreased the concentrations of TNF-α, cortisol and glucagon in plasma, and TNF-α mRNA expression in muscles. Finally, Asn decreased mRNA abundance of muscle toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) signalling-related genes, and regulated their negative regulators. The beneficial effects of Asn on muscle atrophy may be associated with the following: (1) inhibiting muscle protein degradation via activating Akt and inactivating AMPKα and FOXO1; and (2) decreasing the expression of muscle pro-inflammatory cytokines via inhibiting TLR4 and NOD signalling pathways by modulation of their negative regulators.
Immune system activation is involved in the pathophysiology of panic disorder (PD). We investigated INF-γ+874 A/T, TNF-α-308 G/A, and IL-10-1082 G/A single nucleotide polymorphisms (SNPs) to determine their association with PD.
This study enroled 135 PD patients and 135 healthy controls. INF-γ+874 A/T (rs2430561), TNF-α-308 G/A (rs1800629), and IL-10-1082 G/A (rs1800896) were genotyped.
There were no differences in genotypes or allele frequencies between the patient and control groups, regardless of accompanying agoraphobia. However, for female patients, the G allele frequency in IL-10 SNP was higher in the control group than in the patient group. Additionally, the female control group had a higher frequency of the A/G and G/G genotype in the IL-10 SNP than the female patient group.
We suggest that the G allele in IL-10-1082 G/A might have a role in reducing the manifestations of PD in female patients. Further studies are needed to extend and confirm our findings.
At the end of 2013, China reported a countrywide outbreak of measles. From January to May 2014, we investigated the clinical and immunological features of the cases of the outbreak admitted to our hospital. In this study, all 112 inpatients with clinically diagnosed measles were recruited from the 302 Military Hospital of China. The virus was isolated from throat swabs from these patients, and cytokine profiles were examined. By detecting the measles virus of 30 of the 112 patients, we found that this measles outbreak was of the H1 genotype, which is the major strain in China. The rates of complications, specifically pneumonia and liver injury, differed significantly in patients aged <8 months, 8 months to 18 years, and >18 years: pneumonia was more common in children, while liver injury was more common in adults. Pneumonia was a significant independent risk factor affecting measles duration. Compared to healthy subjects, measles patients had fewer CD4+IL-17+, CD4+IFN-γ+, and CD8+IFN-γ+ cells in both the acute and recovery phases. In contrast, measles patients in the acute phase had more CD8+IL-22+ cells than those in recovery or healthy subjects. We recommend that future studies focus on the age-related distribution of pneumonia and liver injury as measles-related complications as well as the association between immunological markers and measles prognosis.
Canine leishmaniosis (CanL) is caused by the parasite Leishmania infantum and is a systemic disease, which can present with variable clinical signs, and clinicopathological abnormalities. Clinical manifestations can range from subclinical infection to very severe systemic disease. Leishmaniosis is categorized as a neglected tropical disease and the complex immune responses associated with Leishmania species makes therapeutic treatments and vaccine development challenging for both dogs and humans. In this review, we summarize innate and adaptive immune responses associated with L. infantum infection in dogs, and we discuss the problems associated with the disease as well as potential solutions and the future direction of required research to help control the parasite.
Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM.
Naturally acquired immunity to the blood-stage of the malaria parasite develops slowly in areas of high endemicity, but is not sterilizing. It manifests as a reduction in parasite density and clinical symptoms. Immunity as a result of blood-stage vaccination has not yet been achieved in humans, although there are many animal models where vaccination has been successful. The development of a blood-stage vaccine has been complicated by a number of factors including limited knowledge of human-parasite interactions and which antigens and immune responses are critical for protection. Opinion is divided as to whether this vaccine should aim to accelerate the acquisition of responses acquired following natural exposure, or whether it should induce a different response. Animal and experimental human models suggest that cell-mediated immune responses can control parasite growth, but these responses can also contribute to significant immunopathology if unregulated. They are largely ignored in most blood-stage malaria vaccine development strategies. Here, we discuss key observations relating to cell-mediated immune responses in the context of experimental human systems and field studies involving naturally exposed individuals and how this may inform the development of a blood-stage malaria vaccine.
Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples ‘sensing’ of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.