Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. ...Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
A substantial amount of phosphorus (P) in the soil is not readily available for plant uptake. Certain species may enhance P availability from poorly soluble P forms. This study focused on improving ...our comprehension of the effect of two lupine species (L. albus and L. angustifolius) on soil’s P mobilization and its link with soil acidity variations, comparing the response of the lupine species in terms of plant traits (i.e., aboveground biomass and nutrient uptake) with that of oats (Avena strigosa L.) in four contrasting soils (i.e., available P in soil, soil acidity, soil fertility, and texture). The phosphorus solubilization capacity was assessed on variations of P availability (PBray1) at four points in time, comparing soils with lupine to oat-containing soils and their baseline values. Compared to soils containing oats, at harvest, lupine soils had significantly increased PBray1 concentrations; the maximum average increment was around 5.3 mg kg−1, with L. albus in Sites 1 and 2, which presented higher organic matter (OM) contents than the other two sites. Lupine-induced soil acidification did not fully explain that P increase. Oats exhibited the highest increase in shoot dry weight in response to soil’s P availability, while lupine was the least affected. Nevertheless, L. albus showed similar or higher nutrient uptake than oats across all soils. The manganese (Mn) concentration was high in both lupine species’ shoot biomass; however, within each lupine species, across all soil types tested, these legumes had different Mn accumulation levels depending on the soil acidity. Lupinus albus had a higher ability to mobilize non-labile P in the light-textured soil with a high OM content, achieving comparable and higher plant P status than oats and providing N through biological N fixation (BNF), positioning it as a suitable crop for diversifying Uruguay’s agricultural crop rotation systems.
A timely, efficient, and coordinated activation of both CD4 and CD8 T cell subsets following HCV infection is believed to be essential for HCV control. However, to what extent a failure of the ...individual T cell subsets can contribute to the high propensity of HCV to persist is still largely undefined. To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA‐A2–binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon γ, interleukin (IL)‐2, IL‐4, and IL‐10. Our results indicate that at clinical onset, CD8 responses are similarly weak and narrowly focused in both self‐limited and chronically evolving infections. At this stage, CD4 responses are deeply impaired in patients with a chronic outcome as they are weak and of narrow specificity, unlike the strong, broad and T helper 1–oriented CD4 responses associated with resolving infections. Only patients able to finally control infection show maturation of CD8 memory sustained by progressive expansion of CD127+ CD8 cells. Thus, a poor CD8 response in the acute stage of infection may enhance the overall probability of chronic viral persistence. In conclusion, the presence of functional CD4 responses represents one of the factors dictating the fate of infection by directly contributing to control of the virus and by promoting maturation of protective memory CD8 responses. (HEPATOLOGY 2006;44:126–139.)
A patient with HER2-positive early breast cancer (BC) developed dermatomyositis (DM), which disappeared after the first administration of adjuvant trastuzumab. No HER2 overexpression/amplification ...was observed in DM skin biopsies. Both BC and skin immune infiltrates were composed mostly of CD3+ T-lymphocytes. Interestingly, tumor-infiltrating lymphocytes expressed PD-1, which was negligible in skin-infiltrating lymphocytes, while both BC cells and keratinocytes were PD-L1-positive. High serum levels of endogenous anti-HER2 antibodies were detected, confirming the induction of a HER2-specific adaptive immune response. It may be argued that HER2-specific T-lymphocytes cross-reacted with one or more unknown skin antigens, causing DM. Trastuzumab may have silenced skin cross-reaction by eliminating any residual HER2-positive micrometastatic disease and, thus, inducing DM remission.
Insulin replacement is the only effective therapy to manage hyperglycemia in type 1 diabetes mellitus (T1DM). Nevertheless, intensive insulin therapy has inadvertently led to insulin resistance. This ...study investigates mechanisms involved in the insulin resistance induced by hyperinsulinization. Wistar rats were rendered diabetic by alloxan injection, and 2 weeks later received saline or different doses of neutral protamine Hagedorn insulin (1.5, 3, 6, and 9 U/day) over 7 days. Insulinopenic-untreated rats and 6U- and 9U-treated rats developed insulin resistance, whereas 3U-treated rats revealed the highest grade of insulin sensitivity, but did not achieve good glycemic control as 6U- and 9U-treated rats did. This insulin sensitivity profile was in agreement with glucose transporter 4 expression and translocation in skeletal muscle, and insulin signaling, phosphoenolpyruvate carboxykinase/glucose-6-phosphatase expression and glycogen storage in the liver. Under the expectation that insulin resistance develops in hyperinsulinized diabetic patients, we believe insulin sensitizer approaches should be considered in treating T1DM.
Aims/Introduction
Epigenetics participate in the pathogenesis of metabolic memory, a situation in which hyperglycemia exerts prolonged deleterious effects even after its normalization. We tested the ...hypothesis that genetic variants in an epigenetic gene could predispose to diabetes complications.
Material and Methods
We assessed the frequency of five single‐nucleotide polymorphisms in the gene encoding deoxyribonucleic acid methytransferase 1 (DNMT1; rs8112895, rs7254567, rs11085721, rs17291414 and rs10854076), and their associations with diabetic kidney disease, retinopathy, distal polyneuropathy and autonomic cardiovascular neuropathy in 359 individuals with long‐term type 1 diabetes.
Results
None of the single‐nucleotide polymorphisms studied was significantly associated with the presence of chronic complications in the overall population. However, after sex stratification, the minor allele C of rs11085721 conferred risk for cardiovascular neuropathy in women after adjustment for confounding variables (odds ratio 2.32; 95% confidence interval 1.26–4.33; P = 0.006).
Conclusions
The fact that heterozygous mutations in DNMT1 are associated with hereditary sensory autonomic neuropathy provides plausibility to the present finding. If confirmed in independent samples, it suggests that genetic variants in epigenetic genes might predispose to more or fewer epigenetic changes in the face of similar metabolic derangements triggered by hyperglycemia, constituting the “genetics of epigenetics” for microvascular diabetes complications.
Epigenetics participate in the pathogenesis of metabolic memory. We tested the hypothesis that genetic variants in epigenetic genes could predispose to diabetes complications. Thus, we assessed the frequency of single‐nucleotide polymorphisms in the gene encoding deoxyribonucleic acid methytransferase 1, and their associations with diabetic kidney disease, retinopathy, distal polyneuropathy and autonomic cardiovascular neuropathy in long‐term type 1 diabetes patients.
Abstract Objective GLUT4 protein, encoded by the Slc2a4 gene, plays a key role in muscle glucose uptake, and its expression decreases in muscles under insulin resistance. Slc2a4 /GLUT4 decreases with ...fasting and rapidly increases with refeeding and the same occurs to plasma glucose, amino acids, insulin and T3. Thus, they might be potential regulators of the Slc2a4 gene, which makes them promising targets for strategies to improve GLUT4 expression. Herein, we investigate the role of metabolic–hormonal parameters triggered by refeeding upon the Slc2a4 expression. Materials/Methods Plasma glucose/insulin/T3, and gastrocnemius Slc2a4 mRNA contents were measured in rats studied at the end of 48-h fasting, and subsequently at: i) 2–4 h after spontaneous refeeding; ii) 2–4 h after T3 injection, without refeeding; and iii) 0.5–2 h after intravenous infusion of insulin, insulin + glucose and insulin + amino acids, without refeeding. Results Refeeding increased plasma glucose/insulin/T3 and muscle Slc2a4 mRNA, reverting insulin resistance. Post-fasting infusions surprisingly induced a further Slc2a4 mRNA decrease (~ 20%, P < 0.05 vs. fasting), but T3 injection induced a ~ 2-fold increase in Slc2a4 mRNA, 2–4 h later ( P < 0.001). Moreover, T3 increased glycemia and insulinemia to the 2 h-refed rats levels, suggesting that T3 elevation is a key factor to the mechanisms of metabolic balance during refeeding. Conclusions Refeeding induces a rapid increase in muscle Slc2a4 expression, not associated with increased plasma glucose, insulin or amino acids, but highly correlated to increased plasma T3 concentration. This result points out T3 hormone as a powerful Slc2a4 enhancer, an effect that may be acutely explored in situations of insulin resistance.
Background & Aims The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate ...HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. Methods HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Results Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. Conclusions IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.
Chronic intake of high-carbohydrate or high-lipid diets is a well-known insulin resistance inducer. This study investigates the immediate effect (1–6 h) of a carbohydrate- or lipid-enriched meal on ...insulin sensitivity. Fasted rats were refed with standard, carbohydrate-enriched (C), or lipid-enriched (L) meal. Plasma insulin, glucose, and non-esterified fatty acids (NEFA) were measured at 1, 2, 4, and 6 h of refeeding. The glucose–insulin index showed that either carbohydrates or lipids decreased insulin sensitivity at 2 h of refeeding. At this time point, insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) detected insulin resistance in C rats, while GTT confirmed it in L rats. Reduced glycogen and phosphorylated AKT and GSK3 content revealed hepatic insulin resistance in C rats. Reduced glucose uptake in skeletal muscle subjected to the fatty acid concentration that mimics the high NEFA level of L rats suggests insulin resistance in these animals is mainly in muscle. In conclusion, carbohydrate- or lipid-enriched meals acutely disrupt glycemic homeostasis, inducing a transient insulin resistance, which seems to involve liver and skeletal muscle, respectively. Thus, the insulin resistance observed when those types of diets are chronically consumed may be an evolution of repeated episodes of this transient insulin resistance.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucose transporter 4 (GLUT4) expression in adipose tissue decreases during fasting. In skeletal muscle, we hypothesized that GLUT4 expression might be maintained in a β‐adrenergic–dependent way to ...ensure energy disposal for contractile function. Herein we investigate β‐blockade or β‐stimulation effects on GLUT4 expression in oxidative (soleus) and glycolytic extensor digitorum longus (EDL) muscles of fasted rats. Fasting increased GLUT4 mRNA in soleus (24%) and EDL (40%), but the protein content increased only in soleus (30%). β1–β2‐, and β1–β2–β3‐blockade decreased (20–30%) GLUT4 mRNA content in both muscles, although GLUT4 protein decreased only in EDL. When mRNA and GLUT4 protein regulations were discrepant, changes in the mRNA poly(A) tail length were detected, indicating a posttranscriptional modulation of gene expression. These results show that β‐adrenergic activity regulates GLUT4 gene expression in skeletal muscle during fasting, highlighting its participation in preservation of GLUT4 protein in glycolytic muscle. Muscle Nerve, 2009
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