The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

Fibroblasts in cancer

LTP and LTD: an embarrassment of riches.

Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

/pdf/endocrine-disrupting-chemicals-an-endocrine-society-3fgbtp8gql.pdf

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

/pdf/cellular-and-molecular-mechanisms-of-fibrosis-48v3c6itoz.pdf

Cellular and molecular mechanisms of fibrosis.

This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major derangements. First, a failure in the turnover of the glomerular basement membrane (GBM) based on an increased production of GBM components by podocytes and endothelial cells leading to the thickening of the GBM and accumulation of worn-out GBM in the mesangium. This failure may account for the direct pathway to glomerular compaction and sclerosis based on the continuous deposition of undegraded GBM-material in the mesangium. Second, an increased leakiness together with an increased propensity of glomerular capillaries to proliferate leads to widespread plasma exudations. Detrimental are those that produce giant insudative spaces within Bowman's capsule (BC) spreading around the entire glomerular circumference and along the glomerulo-tubular junction onto the tubule resulting in tubular obstruction and retroactively to glomerulosclerosis. Tubular atrophy and interstitial fibrosis develop secondarily by transfer of the glomerular damage onto the tubule. Interstitial fibrosis is locally initiated and apparently stimulated by degenerating tubular epithelia. This leads to a focal distribution of interstitial fibrosis and tubular atrophy (IFTA) accompanied by a varying interstitial mononuclear cell infiltration. Spreading of fibrotic areas between intact nephrons, much less to the glomerulus, has not been encountered.

The complex pathology of diabetic nephropathy in humans.

Erstveröffentlichung in Nephrologe (2018) 13:411. https://doi.org/10.1007/s11560-0180269-8 große Proteinurie von 7,2g/g Kreatinin (Albuminurie: 6,7g/g Kreatinin) und ein nephritisches Urinsediment. Serumgesamtprotein (45g/l [66–87g/l]) und Serumalbumin (22g/l [35–52g/l]) waren erniedrigt. Klinisch zeigte sich das Bild eines nephrotischen Syndroms. Blutbild: Hämoglobin 7,4mmol/l, Leukozyten 8,0Gpt/l, Thrombozyten mit 123Gpt/l leicht erniedrigt (146–328Gpt/l). SegmentkernigeNeutrophilemit77%relativ erhöht (40–75%), Lymphozytenmit 12% relativ erniedrigt (17–47%). C-reaktives Protein (CRP) mit 64mg/l erhöht (<5mg/l).

Von Hauteffloreszenzen zum pulmorenalen Syndrom

Normosomer 79-jähriger Patient in gutem Allgemeinzustand; unauffälliges Hautkolorit, keine Lymphknotenschwellung oder Ödeme. Cor: Herztöne leise und rein, Herzaktion normofrequent und rhythmisch. Pulmo: Sklerophonie beidseits (basal mehr links als rechts), sonorer Klopfschall. Abdomen: weich, Darmgeräusche positiv, kein Druckschmerz, keine Abwehrspannung, kein Loslassschmerz, Leber und Milz unauffällig. Extremitäten: unauffällig. Kein fokal neurologisches Defizit.

Mundtrockenheit und akutes Nierenversagen

Immunoglobulin A dominant postinfectious glomerulonephritis (IgA PIGN) is a unique medical entity that is rare in the paediatric population. It usually presents with severe renal failure, heavy proteinuria, hypertension, and hypocomplementemia and frequently has an unfavourable prognosis. IgA PIGN generally occurs in association with staphylococcal infections and diabetes mellitus in adult patients. Other pathogens include Escherichia coli and Streptococcus sp. Immunofluorescence studies of kidney biopsy samples show IgA as dominant or codominant antibody.We encountered a 3-year-old girl with IgA PIGN presenting with acute renal failure, oedema, hypertension, and heavy proteinuria of 7955 mg/g creatinine. Renal biopsy specimens showed diffuse glomerular endocapillary hypercellularity with prominent neutrophil and monocyte infiltration on light microscopy. Strong deposits of IgA and C3 were observed along the glomerular basement membranes and the mesangium by immunofluorescence microscopy, and electron microscopy revealed the presence of subepithelial humps. The patient was managed with steroid (and probatory antibiotic) therapy and is now undergoing follow-up, with a significant improvement 6 months after the initial presentation (glomerular filtration rate (GFR) and cystatin C clearance rate of 165 ml/min/1.73m2 and 106 ml/min/1.73m2, respectively). No signs of bacterial infection were detectable.This variant of IgA PIGN must be distinguished from other clinical entities, especially IgA nephropathy (mesangial IgA deposits) and postinfectious glomerulonephritis (C3, IgG and occasional IgM capillary loop deposits with or without mesangial distribution), since patients with IgA PIGN may require steroid treatment in addition to antibiotic therapy. Differential diagnosis should also include C3 glomerulopathy. IgA PIGN is a recently identified disease entity that generally manifests in adult patients with both IgA and C3 mesangial and glomerular capillary wall deposits. We present a biopsy-proven case of IgA PIGN that manifested in a patient at an exceptionally young age and that has had a good clinical outcome. To the best of our knowledge, this is the youngest IgA PIGN patient reported thus far. 

/pdf/a-rare-case-of-immunoglobulin-a-dominant-post-infectious-khxr9wcb.pdf

A rare case of Immunoglobulin A dominant post-infectious glomerulonephritis (IgA PIGN) in a young patient

Blutuntersuchung.Kreatinin:200μmol/l (Referenz: 74–110μmol/l); eGFR (geschätzte glomeruläre Filtrationsrate): 26ml/min× 1,73m2; Harnstoff: 12,6 mmol/l (Referenz: 3,2–7,3mmol/l); C-reaktives Protein: 47,4mg/l (Referenz: <7,5mg/l). Blutbild: Leukozyten normwertig; Hämoglobin: 6,0mmol/l (Referenz: 8,7–10,0mmol/l); Thrombozyten: 390Gpt/l (Referenz: 150–360ml); C3-,C4-undCH50-Komplement:normwertig.

Hermann Josef Gröne

Papers

The complex pathology of diabetic nephropathy in humans.

Von Hauteffloreszenzen zum pulmorenalen Syndrom

Mundtrockenheit und akutes Nierenversagen

A rare case of Immunoglobulin A dominant post-infectious glomerulonephritis (IgA PIGN) in a young patient

Mundtrockenheit und akutes Nierenversagen