•Both mitochondrial dysfunction and neuroinflammation contribute significantly to neurodegenerative diseases.•Multiple inflammatory mediators are known to affect in mitochondrial energy metabolism ...and mitochondrial dynamics.•In turn, mitochondrial dysfunction can promote inflammation.
Experimental evidence supports an intricate association between inflammation and mitochondrial dysfunction as main contributors of neurological diseases. Inflammatory mediators produced by activated microglia and infiltrated immune cells trigger intracellular signalling cascades that can alter cellular mitochondrial metabolism. Cytokines, particularly tumor necrosis factor-alpha, impede mitochondrial oxidative phosphorylation and associated ATP production and instigate mitochondrial reactive oxygen species production. This culminates in mitochondrial membrane permeabilization, altered mitochondrial dynamics and might ultimately result in cell death. When severely injured mitochondria are not appropriately removed by mitophagy they can release their contents into the cytosol and extracellular environment and thereby amplify the inflammatory process. Here we provide a comprehensive overview on how inflammatory mediators impair mitochondrial metabolism and discuss how defective mitochondria can elicit and potentiate an inflammatory response.
The identification of disease-causing mutations has in recent years progressed immensely due to whole genome sequencing approaches using patient material. The task accordingly is shifting from gene ...identification to functional analysis of putative disease-causing genes, preferably in an in vivo setting which also allows testing of drug candidates or biotherapeutics in whole animal disease models. In this review, we highlight the advances made in the field of bone diseases using small laboratory fish, focusing on zebrafish and medaka. We particularly highlight those human conditions where teleost models are available.
Cadmium (Cd) is a toxic heavy metal that accumulates in living systems. Exposure can occur occupationally or environmentally. Workers within the electroplating, battery production, and pigment ...industries are at the highest risk for exposure and have been reported to have increased levels of Cd in their blood and urine. Environmental exposure can be the result of anthropogenic activities or smoking. Cd has a long half-life and bio accumulates in plants, invertebrates, and vertebrates. The toxic effects following exposure include growth retardation and organ system toxicity, with kidney and liver toxicity most reported with in higher organisms. At the molecular level, Cd leads to the production of reactive oxygen species, DNA damage, and inhibition of DNA repair. This article gives a brief overview of the correlations between exposure to cadmium occupationally and environmentally and levels measured in blood and urine. It also examines the bioaccumulation of cadmium in aquatic invertebrates and vertebrates indicating that accumulation varies not only by location but also within and between various species.
Display omitted
•Exposure to cadmium can occur occupationally of environmentally.•Cadmium exposure can be measured using blood and urine samples.•Cadmium bio accumulates in vertebrate and aquatic invertebrate organisms.•Free cadmium can accumulates aquatic organisms leading to biotransfer into vertebrates.•Cadmium exposure leads to ROS production and DNA damage.
Fibroblasts are diverse mesenchymal cells that participate in tissue homeostasis and disease by producing complex extracellular matrix and creating signaling niches through biophysical and ...biochemical cues. Transcriptionally and functionally heterogeneous across and within organs, fibroblasts encode regional positional information and maintain distinct cellular progeny. We summarize their development, lineages, functions, and contributions to fibrosis in four fibroblast-rich organs: skin, lung, skeletal muscle, and heart. We propose that fibroblasts are uniquely poised for tissue repair by easily reentering the cell cycle and exhibiting a reversible plasticity in phenotype and cell fate. These properties, when activated aberrantly, drive fibrotic disorders in humans.
A detailed mechanistic, molecular, and functional view of the commonalities and organ-specific features of fibroblasts in health and disease is just beginning to emerge.
Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains ...elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (
≤ 0.001;
≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-index
= 0.86; AIC
= 448.43; AIC
= 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers.
•ROS is both a trigger and an effector of NLRP3 inflammasome activation.•Ca2+ influx is upstream of NLRP3 inflammasome activation.•ADP-ribose (ADPR) activates TRPM2 under ROS in the NLRP3 ...pathway.•ADPR and Ca2+ co-activate TRPM2.•There exist drastic differences in TRPM2’s structure and function during evolution.
The NLRP3 inflammasome is an innate immune platform that senses various pathogens and sterile insults. NLRP3 stimulation leads to activation of caspase-1, the secretion of pro-inflammatory cytokines and an inflammatory cell death called pyroptosis. Effectors of the NLRP3 inflammasome efficiently drive an immune response, not only providing protection in physiological settings but also promoting pathology when over activated. Generation of reactive oxygen species (ROS) and intracellular calcium mobilization can activate the NLRP3 inflammasome. Recent studies suggest that TRPM2 is a calcium-permeable cation channel mediating ROS-dependent NLRP3 activation. Here, we review the role of TRPM2 in NLRP3 inflammasome activation and provide an update on new functional and structural discoveries. Understanding the molecular mechanism of TRPM2 dependent NLRP3 inflammasome activation will shed lights on this complex pathway and help the developing of therapeutic strategies.
PDF
