Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now ...recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas.
Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) ...cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.
The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood
. Indoleamine ...2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells
. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome
and may promote atherosclerosis and vascular inflammation
, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity
, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.
A future for PET imaging in Alzheimer’s disease Kas, Aurélie; Migliaccio, Raffaella; Tavitian, Bertrand
European journal of nuclear medicine and molecular imaging,
02/2020, Letnik:
47, Številka:
2
Journal Article
Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy ...control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR,
11
CPK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of
11
CPK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents.
Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose ...tissue-derived stromal cell (ADSC) double cell sheet transplantation.
Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed.
One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6 (17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm²; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052).
In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture's rate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Takotsubo cardiomyopathy is a stress-induced cardiovascular disease with symptoms comparable to those of an acute coronary syndrome but without coronary obstruction. Takotsubo was initially ...considered spontaneously reversible, but epidemiological studies revealed significant long-term morbidity and mortality, the reason for which is unknown. Here, we show in a female rodent model that a single pharmacological challenge creates a stress-induced cardiomyopathy similar to Takotsubo. The acute response involves changes in blood and tissue biomarkers and in cardiac in vivo imaging acquired with ultrasound, magnetic resonance and positron emission tomography. Longitudinal follow up using in vivo imaging, histochemistry, protein and proteomics analyses evidences a continued metabolic reprogramming of the heart towards metabolic malfunction, eventually leading to irreversible damage in cardiac function and structure. The results combat the supposed reversibility of Takotsubo, point to dysregulation of glucose metabolic pathways as a main cause of long-term cardiac disease and support early therapeutic management of Takotsubo.
Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic ...lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with 18FDPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo1,5-apyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro 18FDPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that 18FDPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.
Background
One-anastomosis gastric bypass/mini-gastric bypass (OAGB/MGB) remains controversial because it may cause chronic biliary reflux (BR). The risk of developing esogastric cancer due to BR ...after OAGB/MGB is based on the results of experimental rat studies using esojejunostomy (EJ). The aim of this study was to analyze the potential long-term consequences of BR on the esogastric mucosae in OAGB/MGB-operated rats and to compare these results to those from the use of EJ.
Methods
Wistar rats received OAGB/MGB (
n
= 16), EJ (
n
= 16), and sham (
n
= 8) operations. Mortality and weight changes were evaluated throughout the experiment. BR was measured using magnetic resonance imaging (MRI). Rats received follow-ups for 30 weeks. A double-blinded histological analysis was performed in the esogastric segments.
Results
BR was diagnosed in OAGB/MGB and EJ rats using the MRI technique; no BR occurred in the sham group. After a 30-week follow-up, no incidences of dysplasia or cancer were observed in the three groups. Additionally, esophageal intestinal metaplasia and mucosal ulcerations were observed in 41.7% and 50% of EJ rats, respectively, and no incidences of these conditions were observed in OAGB/MGB and sham rats. The incidence of esophagitis was significantly higher and more severe in the EJ group compared to those in the OAGB/MGB and sham groups (EJ = 100%, OAGB/MGB = 16.7%, sham = 8.3%;
p
< 0.001).
Conclusions
After a 30-week follow-up period, OAGB/MGB rats did not develop any precancerous or cancerous lesions when more than 40% of EJ rats had intestinal metaplasia.
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