A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia

Alzheimer’s Disease (AD) represents the most common type of dementia and is becoming a steadily increasing challenge for health systems globally. Inflammation is developing as the main focus of research into Alzheimer’s disease and has been demonstrated to be a major driver of the pathologies associated with AD. This evidence introduces an interesting research question, whether chronic inflammation due to pathologies such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) could lead to a higher risk of developing dementia. In both IBD and RA, increased levels of the inflammatory biomarker C-reactive protein (CRP) can be highlighted, the latter being directly implicated in neuroinflammation and AD. In this meta-analysis both the association between chronic inflammatory diseases and elevated levels of CRP during midlife were investigated to examine if they correlated with an augmented risk of dementia. Moreover, the association between increased CRP and modifications in the permeability of the Blood Brain Barrier (BBB) in the presence of CRP is explored. The results displayed that the odds ratio for IBD and dementia was 1.91 [1.15-3.15], for RA it was 1.90 [1.09-3.32] following sensitivity analysis and for CRP it was 1.62 [1.22-2.15]. These results demonstrate a higher risk of dementia in patients presenting chronic inflammation and that exists an independent association with high CRP in midlife. This paper builds on published research that suggest a critical role for CRP both in stroke and AD and provides an analysis on currently published research on multiple diseases (IBD and RA) in which CRP is raised as well as chronically elevated. CRP and the associated risk of dementia and further research indicated that the monomeric form of CRP can infiltrate the BBB/be released from damaged micro-vessels to access the brain. This meta-analysis provides first-time evidence that chronic elevation of CRP in autoimmune diseases is directly associated with an increased risk of later development of Alzheimer’s disease. Therefore, greater priority should be provided to the effective control of inflammation in patients with chronic inflammatory or autoimmune conditions and further long-term assessment of circulating CRP might inform of an individual’s relative risk of developing dementia

Monomeric C-reactive protein: current perspectives for utilization and inclusion as a prognostic indicator and therapeutic target

Monomeric C-reactive protein (mCRP), once thought to be a figment of the imagination and whose biological activity was ascribed to its sodium azide preservative, has now pronounced itself as a critical molecule playing a direct role in mediating many of the acute and chronic aberrant pathological responses to inflammation. In this focused mini review, we describe the currently attributed pathobiological interactions of mCRP in disease, where its tissue and cellular distribution and deposition have recently been clearly characterized and linked to inflammation and other pathway-associated progression of neurological and cardiovascular complications and deleterious outcomes. and focus upon current opinions as to the diagnostic and prognostic potential of mCRP-plasma circulating protein and define the possible future therapeutics including ongoing research attempting to block CRP dissociation with small molecule inhibitors or prevention of cell surface binding directly using antibodies or modified orphan drug targeting directed towards CRP, inhibiting its cellular interactions and signaling activation. There is no doubt that understanding the full influence of the biological power of mCRP in disease development and outcome will be considered a critical parameter in future stratified treatment

Mesenchymal stem cell stroke therapy: current limitations in its clinical translation

For more than a decade now, research studies, proof of concept work, and clinical trials have endeavored to understand how mesenchymal stem cells might be used to help protect, repair, and/or regenerate damaged brain tissue following stroke. To date, the majority of studies have not demonstrated significant improvements in either morbidity or medium-long-term outcome, although safety has been relatively well proven. Limitations are likely to be linked to the pathobiological complexity and seriousness of stroke tissue damage, low efficacy of treatment, and short half-life of bio-active proteins released by stem cells. This article will highlight the heterogeneity and limitation of completed studies and the current status of ongoing work. At the same time, the potential of other combinational type treatments, such as drug-loading and targeting, and the use of hydrogels is discussed

Micro-fragmented adipose tissue as a natural scaffold for targeted drug delivery in brain cancer

Major limitations in the effective treatment of neurological cancer include systemic cytotoxicity of chemotherapy, inaccessibility, and inoperability. The capability to successfully target a drug to the tumor site(s) without incurring serious side effects—especially in the case of aggressive tumors, such as glioblastoma and neuroblastoma—would represent a significant breakthrough in therapy. Orthotopic systems, capable of storing and releasing proteins over a prolonged period at the site of a tumor, that utilize nanoparticles, liposomes, and hydrogels have been proposed. One candidate for drug delivery is Micro-Fragmented Adipose Tissue (MFAT). Easily obtained from the patient by abdominal subcutaneous liposuction (autologous), and with a high content of Mesenchymal Stem Cells (MSCs), mechanically derived nanofat is a natural tissue graft with a structural scaffold organization. It has a well-preserved stromal vascular fraction and a prolonged capacity to secrete anti-tumorigenic concentrations of pre-absorbed chemotherapeutics within extracellular vesicles. This review discusses current evidence supporting the potential of drug-modified MFAT for the treatment of neurological cancer with respect to recent preclinical and in vitro studies. Possible limitations and future perspectives are considered

Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses

Hyaluronan (HA) is a large nonsulfated glycosaminoglycan and an important regulator of angiogenesis, in particular, the growth and migration of vascular endothelial cells. We have identified some of the key intermediates responsible for induction of mitogenesis and wound recovery. Treatment of bovine aortic endothelial cells with oligosaccharides of hyaluronan (o-HA) resulted in rapid tyrosine phosphorylation and plasma membrane translocation of phospholipase C1 (PLC1). Cytoplasmic loading with inhibitory antibodies to PLC1, G, and Gi/o/t/z inhibited activation of extracellular-regulated kinase 1/2 (ERK1/2). Treatment with the Gi/o inhibitor, pertussis toxin, reduced o-HA-induced PLC1 tyrosine phosphorylation, protein kinase C (PKC) and 1/2 membrane translocation, ERK1/2 activation, mitogenesis, and wound recovery, suggesting a mechanism for o-HA-induced angiogenesis through G-proteins, PLC1, and PKC. In particular, we demonstrated a possible role for PKC in mitogenesis and PKC1/2 in wound recovery. Using antisense oligonucleotides and the Ras farnesylation inhibitor FTI-277, we showed that o-HA-induced bovine aortic endothelial cell proliferation, wound recovery, and ERK1/2 activation were also partially dependent on Ras activation, and that o-HA-stimulated tyrosine phosphorylation of the adapter protein Shc, as well as its association with Sos1. Binding of Src to Shc was required for its activation and for Ras-dependent activation of ERK1/2, cell proliferation, and wound recovery. Neither Src nor Ras activation was inhibited by pertussis toxin, suggesting that their activation was independent of heterotrimeric G-proteins. However, the specific Src kinase inhibitor PP2 inhibited G subunit co-precipitation with PLC1, suggesting a possible role for Src in activation of PLC1 and interaction between two distinct o-HA-induced signaling pathways

A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia

Alzheimer’s Disease (AD) represents the most common type of dementia and is becoming a steadily increasing challenge for health systems globally. Inflammation is developing as the main focus of research into Alzheimer’s disease and has been demonstrated to be a major driver of the pathologies associated with AD. This evidence introduces an interesting research question, whether chronic inflammation due to pathologies such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) could lead to a higher risk of developing dementia. In both IBD and RA, increased levels of the inflammatory biomarker C-reactive protein (CRP) can be highlighted, the latter being directly implicated in neuroinflammation and AD. In this meta-analysis both the association between chronic inflammatory diseases and elevated levels of CRP during midlife were investigated to examine if they correlated with an augmented risk of dementia. Moreover, the association between increased CRP and modifications in the permeability of the Blood Brain Barrier (BBB) in the presence of CRP is explored. The results displayed that the odds ratio for IBD and dementia was 1.91 [1.15-3.15], for RA it was 1.90 [1.09-3.32] following sensitivity analysis and for CRP it was 1.62 [1.22-2.15]. These results demonstrate a higher risk of dementia in patients presenting chronic inflammation and that exists an independent association with high CRP in midlife. This paper builds on published research that suggest a critical role for CRP both in stroke and AD and provides an analysis on currently published research on multiple diseases (IBD and RA) in which CRP is raised as well as chronically elevated. CRP and the associated risk of dementia and further research indicated that the monomeric form of CRP can infiltrate the BBB/be released from damaged micro-vessels to access the brain. This meta-analysis provides first-time evidence that chronic elevation of CRP in autoimmune diseases is directly associated with an increased risk of later development of Alzheimer’s disease. Therefore, greater priority should be provided to the effective control of inflammation in patients with chronic inflammatory or autoimmune conditions and further long-term assessment of circulating CRP might inform of an individual’s relative risk of developing dementia