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Mice lacking thioredoxin-interacting protein provide evidence linking cellular redox state to appropriate response to nutritional signals.

Thioredoxin-interacting protein (Txnip) is a ubiquitous protein that binds with high affinity to thioredoxin and inhibits its ability to reduce sulfhydryl groups via NADPH oxidation. HcB-19 mice contain a nonsense mutation in Txnip that eliminates its expression. Unlike normal animals, HcB-19 mice have approximately 3-fold increase in insulin levels when fasted. The C-peptide/insulin ratio is normal, suggesting that the hyperinsulinemia is due to increased insulin secretion. Fasted HcB-19 mice are hypoglycemic, hypertriglyceridemic, and have higher than normal levels of ketone bodies. Ablation

Depletion of anti-gal antibodies in baboons by intravenous therapy with bovine serum albumin conjugated to gal oligosaccharides.

BACKGROUND: Anti-Galalpha 1-3Gal (Gal) antibodies (Ab) play a key role in the rejection of pig cells or organs transplanted into primates. A course of extracorporeal immunoadsorption (EIA) of anti-Gal Ab using an immunoaffinity column of a Gal type 6 oligosaccharide depletes Ab successfully, but Ab returns during the next few days. Although therapy with an anti-CD154 monoclonal antibody (mAb) prevents an induced Ab response to Gal or non-Gal epitopes, T cell-independent natural anti-Gal IgM and IgG return to baseline (pretransplant) levels. We have investigated the capacity of continuous i.v.

Elucidating heterogeneity of IgA1 hinge-region O-glycosylation by use of MALDI-TOF/TOF mass spectrometry: role of cysteine alkylation during sample processing.

UNLABELLED: Determining disease-associated changes in protein glycosylation provides a better understanding of pathogenesis. This work focuses on human immunoglobulin A1 (IgA1), where aberrant O-glycosylation plays a key role in the pathogenesis of IgA nephropathy (IgAN). Normal IgA1 hinge region carries 3 to 6 O-glycans consisting of N-acetylgalactosamine (GalNAc) and galactose (Gal); both sugars may be sialylated. In IgAN patients, some O-glycans on a fraction of IgA1 molecules are Gal-deficient. Here we describe a sample preparation protocol with optimized cysteine alkylation of a Gal-defic…

Lectin histochemistry in the rats brain in experimental postresuscitation syndrome. (Early and late changes).

The morphological and histochemical changes in the rat brain, resulting from global cerebral ischemia due to cardiac arrest and cessation of … ues located on the cell surfaces, made it possible to localize the following sugar residues: beta-D-galactose (using Ricinus communis agg.-RCA-1); beta-D-galactosyl (Ricinus communis agglutinin <RCA-1>), N-acetyl-glucosaminyl and N-acetyl-neuraminic acid (Wheat germ agglutinin WGA), N-acetyl-glucosaminyl (Helix pomatia agglutinin <HPA> and Dolichos biflorus …

[Native valve Aspergillus fumigatus endocarditis with blood culture positive and negative for galactomannan antigen. Case report and literature review].

Native valve endocarditis caused by Aspergillus spp. is an uncommon disease with a high mortality rate. Generally, Aspergillus is isolated from affected valve in post-mortem or biopsy specimens. However, its isolation from blood cultures is exceedingly rare. We report a case of fungal endocarditis in a native mitral valve with the isolation of Aspergillus fumigatus both in valve vegetation and in blood culture bottles. The patient underwent valve replacement and antifungal treatment with voriconazole and caspofungin, but he died on post-operative day 45 with disseminated aspergillosis confirme

Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells.

Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of oxidative phosphorylation or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro. Here, we examined the effects of the tyrosine ki

Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription. implications for Cockayne syndrome.

In addition to xeroderma pigmentosum, mutations in the human XPG gene cause early onset Cockayne syndrome (CS). Here, we provide evidence for the involvement of RAD2, the S. cerevisiae counterpart of XPG, in promoting efficient RNA polymerase II transcription. Inactivation of RAD26, the S. cerevisiae counterpart of the human CSB gene, also causes a deficiency in transcription, and a synergistic decline in transcription occurs in the absence of both the RAD2 and RAD26 genes. Growth is also retarded in the rad2 Delta and rad26 Delta single mutant strains, and a very severe growth inhibition is s

The heart in Anderson Fabry disease.

Anderson Fabry disease is a life threatening, X-linked inborn metabolic defect of the lysosomal enzyme áalpha-galactosidase A. The deficiency of alpha-galactosidase A leads to a progressive accumulation of globotriaosylceramide (Gb(3)), the major glycosphingolipid substrate of the enzyme, within vulnerable cells, tissues, and organs, including the cardiovascular system. Cardiac involvement is frequent and patients with cardiac affection develop progressive hypertrophic infiltrative cardiomyopathy, valvular abnormalities, arrhythmias, and conduction abnormalities and may develop coronary heart

What is new in the pathogenesis and treatment of IgA glomerulonephritis.

Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment

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… Potential role of chromosome 22q12.2 | Serum galactose-deficient IgA1 level (HAA based ELISA) | Suppression of synthesis of galactose-deficient IgA1. … Enzymatic boost of galactose transfer to IgA1 hinge region O-glycans 2 | Circulating antibody directed against galactose-deficient IgA1 | Potential role of mucosal exposure to infectious or dietary antigens | Potential role of three MHC-II loci in antigen presentation and humoral response to galactose-deficient …

IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers.

IgG N-glycans are an emerging source of disease-specific biomarkers. Over the last decade, the continued development of glycomic databases and the evolution of glyco-analytic methods have resulted in increased throughput, resolution, and sensitivity. IgG N-glycans promote adaptive immune responses through antibody-dependent cellular cytotoxicity (ADCC) and complement activation to combat infection or cancer and promote autoimmunity. In addition to the functional assays, researchers are examining the ability of protein-specific glycosylation to serve as biomarkers of disease. This literature re

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… Age impacts the IgG N-glycan profile; pediatric age ranges gain galactose into young adulthood [ 49 ] while older adults decrease galactose content [ 50 , 51 , 52 ]. … Fokkink et al. determined patients with GBS had lowered galactose and sialic acid content on IgG1 and IgG2 when compared to healthy controls [ 78 ]. …

Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy.

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin-angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi-hit hypothesis-while foundational for targeted therapy development-fails to capture IgAN's recurrent, self-amplifying nature. We introduce the "spi

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… By inhibiting NF‐κB signaling, Nefecon reduces systemic levels of galactose‐deficient IgA1 (Gd–IgA1) while minimizing systemic glucocorticoid exposure. … Potential targets could include surface markers on the B‐cells or plasma cells producing galactose‐deficient IgA1, or even the aberrant IgA1 molecule itself. …

Comparison of 1,3-β-d-glucan with galactomannan in serum and bronchoalveolar fluid for the detection of Aspergillus species in immunosuppressed mechanical ventilated critically ill patients.

PURPOSE: Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity/mortality in immunocompromised critically ill patients. New diagnostic strategies for early detection of IPA include the noninvasive biomarkers 1,3-β-d-glucan (BDG), serum, and bronchoalveolar (BAL) fluid galactomannan (GM). The aim of this study was to compare these markers for early detection of IPA in immunosuppressed critically ill patients. METHODS: Between December 2014 and December 2015, 49 immunosuppressed patients with respiratory failure were treated at our intensive care unit (ICU). We compared the B

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, wi

SARS-CoV-2 and Aspergillus section Fumigati coinfection in an immunocompetent patient treated with corticosteroids.

BACKGROUND: Patients with severe viral pneumonia are likely to receive high-dose immunomodulatory drugs to prevent clinical worsening. Aspergillus species have been described as frequent secondary pneumonia agents in severely ill influenza patients receiving steroids. COVID-19 patients admitted to Intensive Care Unit (ICU) are receiving steroids as part of their treatment and they share clinical characteristics with other patients with severe viral pneumonias. COVID-19 patients receiving steroids should be considered a putative risk group of invasive aspergillosis. CASE REPORT: We are reporti

Haploid genetic screens in human cells identify host factors used by pathogens.

Loss-of-function genetic screens in model organisms have elucidated numerous biological processes, but the diploid genome of mammalian cells has precluded large-scale gene disruption. We used insertional mutagenesis to develop a screening method to generate null alleles in a human cell line haploid for all chromosomes except chromosome 8. Using this approach, we identified host factors essential for infection with influenza and genes encoding important elements of the biosynthetic pathway of diphthamide, which are required for the cytotoxic effects of diphtheria toxin and exotoxin A. We also i

Polygala oligosaccharide esters improve memory disorder by restoring gut microbiota homeostasis through the regulation of the "gut-brain" axis.

BACKGROUND: Yuanzhi (Polygala tenuifolia Willd.) possesses the effects of calming the spirit, enhancing intelligence, regulating the heart-k … ific focus on the gut-brain axis. METHODS: A mouse model of memory dysfunction was induced using D-galactose combined with AlCl₃. Behavioral tests, molecular biology techniques (histopathology, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and Western blot), and multi-omics approaches (16S rRNA sequencing and lipidomic analysis) were emp …

[Research on ameliorating pulmonary fibrosis in silicosis mice of Cordyceps cicadae polysaccharides].

Objective: A mouse silicosis model was constructed by injecting silicon dioxide (SiO(2)) particles into the trachea to explore the effect an … : The total sugar content of the CCP was 86.78%, composed of D-mannose, D-rhamnose, D-glucose and D-galactose, with a molar ratio of 12.71∶1.53∶1.00∶12.64. The infrared spectrum indicated the characteristic groups of its polysaccharides. Compared with the control group, the body weight of mice in the model group was decreased, lung coefficient was increased …

Allergy in Cancer Care: Antineoplastic Therapy-Induced Hypersensitivity Reactions.

As the backbone of oncological treatments, systemic chemotherapy is still one of the main pawns in cancer care, alone or in combination with newer targeted agents. All chemotherapy agents can be associated with a type of adverse event called an infusion reaction, which can be characterized as unpredictable, non-dose related, and unexplained by the cytotoxic profile of the drug. For some of these events, a certain immunological mechanism can be identified by blood or skin testing. In this case, we can speak of true hypersensitivity reactions that occur as a response to an antigen/allergen. The

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… Therefore, we can easily explain the lack of cross-reactivity between cetuximab and panitumumab, the latest being a fully human-derived monoclonal antibody, lacking galactose-alpha-1,3-galactose [ 115 ]. … Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-1, 3-Galactose N. Engl. J. Med. 2008 358 1109 1117 10.1056/NEJMoa074943 18337601 PMC2361129 115. Saif M.W. Peccerillo J. Potter V. …

Primary IgA nephropathy: current challenges and future prospects.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrat

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… Characterization of both circulating and glomerular immune complexes in IgAN patients has revealed complexes comprising galactose-deficient IgA1 (Gd-IgA1) and C3. … Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol. 2012;23(9):1579–1587. doi: 10.1681/ASN.2012010053. 83. Zhao N, Hou P, Lv J, et al. …

Emerging Modes of Treatment of IgA Nephropathy.

IgA nephropathy is the most common primary glomerulonephritis with potentially serious outcome leading to end stage renal disease in 30 to 50% of patients within 20 to 30 years. Renal biopsy, which might be associated with risks of complications (bleeding and others), still remains the only reliable diagnostic tool for IgA nephropathy. Therefore, the search for non-invasive diagnostic and prognostic markers for detection of subclinical types of IgA nephropathy, evaluation of disease activity, and assessment of treatment effectiveness, is of utmost importance. In this review, we summarize treat

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… A key role in the pathogenesis of IgAN is played by aberrantly glycosylated forms of IgA1 with galactose-deficient O -glycans (galactose-deficient IgA1; Gd-IgA1), which are recognized by antiglycan autoantibodies of IgG and/or IgA1 isotype, resulting in the formation of circulating immune complexes [ … Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG Kidney Int. 1997 52 509 516 10.1038/ki.1997.361 9264010 11. Tomana M. Novak J. Julian B.A. Matousovic K. Konecny K. Mestecky J. …