Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

/pdf/curcumin-requires-tumor-necrosis-factor-a-signaling-to-503zpd8eod.pdf

Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolysaccharide.

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Gene Expression Profiles and Immunohistochemical Analysis Highlight Role of Endoplasmic Reticulum Stress in Pulmonary Fibrosis.

Aging poses a global public health challenge, associated with molecular and physiological changes in the lungs. It increases susceptibility to acute and chronic lung diseases, yet the underlying molecular and cellular drivers in aged populations are not fully appreciated. To systematically profile the genetic changes associated with age, we present a single-cell transcriptional atlas comprising nearly half a million cells from the healthy lungs of human subjects spanning various ages, sexes, and smoking statuses. Most annotated cell lineages in aged lungs exhibit dysregulated genetic programs. Specifically, the aged alveolar epithelial cells, including both alveolar type II (AT2) and type I (AT1) cells, demonstrate loss of epithelial identities, heightened inflammaging characterized by increased expression of AP-1 transcription factor and chemokine genes, and significantly increased cellular senescence. Furthermore, the aged mesenchymal cells display a remarkable decrease in Collagen and Elastin transcription. The decline of the AT2 niche is further exacerbated by a weakened endothelial cell phenotype and a dysregulated genetic program in macrophages. These findings highlight the dysregulation observed in both AT2 stem cells and their supportive niche cells, potentially contributing to the increased susceptibility of aged populations to lung diseases.

/pdf/a-transcriptional-cell-atlas-identifies-the-decline-in-the-83rv7bcv.pdf

A transcriptional cell atlas identifies the decline in the AT2 niche in aged human lungs

Extract One of the significant advances in the biology of idiopathic pulmonary fibrosis (IPF) has been the recognition of fibroblast heterogeneity in the lung. Fibroblast heterogeneity can be interpreted as fibroblast subtypes, probably derived from distinct mesenchymal lineages, as well as various activation states, such as proliferation, matrix production and invasiveness. With great interest, we read the original work by Mayr et al. [1] presenting a concept that the Sfrp1+ transitional fibroblasts with low invasive capacity emerge early after bleomycin-induced injury and ultimately transit to Spp1/Cthrc1+ matrix-producing (myo)fibroblasts with the driving force of transforming growth factor (TGF)β1 signalling from myeloid and epithelial lineages. This study largely aligns with our recent publication proposing that multiple fibroblast subtypes from IPF lungs contribute to the invasive phenotype of fibroblasts and the matrix deposition in pulmonary fibrosis [2].

The concept of Sfrp1+ transitional fibroblasts: the key to dissociating lineage heterogeneity and fate of invasive fibroblasts in pulmonary fibrosis?

Mechanisms that regulate host defense to noninfectious tissue injury are poorly understood. Here we summarize our recent work investigating the role of the innate immune response in regulating the inflammatory and fibrotic response to noninfectious lung injury. We have identified key roles for two cell surface receptors in regulating lung inflammation and fibrosis. CD44 has an essential role in resolving inflammation following noninfectious lung injury. A major function of CD44 in vivo is to clear hyaluronan degradation products that are produced following lung injury. Failure ot clear hyaluronan leads to unremitting inflammation. In contrast, the chemokine receptor CXCR3 has an essential role in limiting the extent of fibrosis following lung injury. This protective effect of CXCR3 in limiting tissue fibroproliferation is mediated, in part, by the innate production of interferon-γ following lung injury. These studies reveal a previously unsuspected role for the innate immune response in regulating inflammation and fibrosis.

Innate Immune Regulation of Lung Injury and Repair

ligand-2 clears apoptotic cells in noninfectious lung A macrophage subpopulation recruited by CC chemokine

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