Alzheimer’s disease (AD) is the most common form of dementia among the elderly The disease is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons, and chronic neuroinflammation The significance of neuroinflammatory processes in the on-set and progression of AD have been debated, as activated and reactive glial cells demonstrated protective and damaging properties However, patients with AD treated with anti-inflammatory drugs demonstrated a lesser than average extent of disease development, indicating an important role of neuroinflammation in AD Current strategies for the treatment of Alzheimer’s disease are minimally effective, as we lack the methods of diagnosis at an early stage Numerous cases present significant neuronal loss prior to diagnosis and, as restoration of function is unlikely, treatment options focus on limiting further neuronal loss It is my hypothesis that deposition of Aβ peptide can activate the innate immune system via pattern recognition receptors (PRRs), including complement, and evoke Alzheimer's pathology In the current study, we focused on the role of the innate immunity system of the brain in the initiation and the propagation of inflammatory process in AD and the interplay between TLRs/NLRs and the complement system
Silencing the expression of various receptors demonstrated the involvement of NLRP3 in Aβ recognition, and use of confocal microscopy confirmed the association of Aβ interactions with this inflammasome and complement receptors These results were confirmed in human astrocytes stimulated with Aβ and in brain tissue slides of patients with AD Using human astrocytes and fluorescence resonance energy transfer (FRET), the associations of cell surface TLRs (such as TLR2, TLR4)with CRs (C5aR1, C3aR) were investigated; TLR2 and TLR4 were
6 | P a g e
found to interact with C5aR1 In addition, Aβ-induced responses were augmented in the presence of complement and Aβ appeared to induce the interactions of TLR4 and C5aR1 on the cell surface The trafficking of PRRs and Aβ in human astrocytes was further investigated to determine whether internalization and trafficking of Aβ is crucial for triggering a proinflammatory response The results demonstrated that, along with Aβ and TLR4, complement internalized in the Rab5+ endosomes, and recruited NF-kB-inducing kinase (NIK) to these endosomes in a complement-dependent manner MAC complexes were previously demonstrated to activate an Akt+NIK+ signalosome in human endothelial cells To the best of our knowledge, this is the first to identify such signalosomes in Rab5+ endosomes in response to complement and Aβ These results suggest a novel possibility of a therapeutic target in the case of an Aβ-induced neuroinflammation
C5a is the most potent anaphylatoxin, thus upon the identification of the complement-inflammasome interactions, the role of C5a in the Aβ recognition was investigated in human astrocytes The results demonstrated that C5a augmented the Aβ-induced IL-1β production, activated pro-IL-1β and was caspase-1-dependent In addition, a C5a-induced IL-1β release was observed following Signal 2 stimulation by Ca2+ and lysosomal damage Since the signal activation resulting in inflammation in AD appears to involve multiple receptors, the therapy should be combinational and not targeting single molecules Thus, C5aR1 blocking antibodies and PMX53 were utilized to identify a combinatory therapeutic approach in human astrocytes The results demonstrated that the secretion of IL-1β was further reduced in the combinatory treatment of PMX53+MCC950
7 | P a g e
compared with their single treatments, suggesting a combinatory treatment to tackle the effect of Aβ in human cells
The results of the present study add on to the current knowledge of the molecular mechanisms involved in AD, regarding Aβ association, and may lead to the design of targeted therapeutic interventions for AD

The role of pattern recognition receptors in amyloid-beta-induced inflammation

The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

From endoplasmic reticulum stress to the inflammatory response.

https://doc.rero.ch/record/327031/files/Farsakoglu_CellRep_2019.pdf

Influenza Vaccination Induces NK-Cell-Mediated Type-II IFN Response that Regulates Humoral Immunity in an IL-6-Dependent Manner

Otitis media (OM) is a common disease that can cause hearing loss in children. Currently, the main clinical treatment for OM is antibiotics, but the overuse of antibiotics might lead to bacterial resistance, which is a worldwide public health challenge. Studying the pathogenesis of OM will help us develop new effective treatments. Ferroptosis is one type of programmed cell death characterized by the occurrence of lipid peroxidation driven by iron ions. Many studies have shown that ferroptosis is associated with infectious diseases. It is presently unclear whether ferroptosis is involved in the pathogenesis of OM. In this study, we explored the relationship between ferroptosis and OM by PGPS-induced OM in C57BL/6 mice and treating the induced OM with ferroptosis inhibitors deferoxamine (DFO), Ferrostatin-1 (Fer-1), and Liperoxstatin-1 (Lip-1). We examined the expression of ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (Cox2), glutathione peroxidase 4 (GPX4) protein as well as lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The results showed that in PGPS-induced OM model mice, several ferroptosis-related proteins including ACSL4 and Cox2 were up-regulated compared to mice treated with saline. Meanwhile, a ferroptosis-related protein GPX4 was down-regulated upon PGPS treatment. The DFO treatment in PGPS-inoculated mice effectively inhibited the development of OM. The inhibitors treatment caused a significant decrease in the expression of ACSL4, Cox2, 4 HNE, MDA, reduction in free iron. Meanwhile, the ferroptosis inhibitors treatment caused increase in the expression of inflammation-related factors tumor necrosis factor-α (TNF-α) and antioxidant protein GPX4. Our results suggest that there is a crosstalk between ferroptosis signaling pathway and the pathogenesis of OM. Ferroptosis inhibition can alleviate PGPS-induced OM. 

https://www.nature.com/articles/s41420-022-01025-1.pdf

Ferroptosis is involved in PGPS-induced otitis media in C57BL/6 mice

Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.

/pdf/tumour-inflammation-signature-and-expression-of-s100a12-and-ao5bgoe8sg.pdf

Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer.

Endoplasmic reticulum (ER) stress occurs in many inflammatory responses. Here, we investigated the role of ER stress and its associated apoptosis in otitis media (OM) to elucidate the mechanisms of OM and the signaling crosstalk between ER stress and other cell damage pathways, including inflammatory cytokines and apoptosis. We examined the expression of inflammatory cytokine- and ER stress-related genes by qRT-PCR, Western blotting, and immunohistochemistry (IHC) in the middle ear of C57BL/6J mice after challenge with peptidoglycan polysaccharide (PGPS), an agent inducing OM. We also evaluated the effect of the suppression of ER stress with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor. The study revealed the upregulation of ER stress- and apoptosis-related gene expression after the PGPS treatment, specifically ATF6, CHOP, BIP, caspase-12, and caspase-3. TUDCA treatment of PGPS-treated mice decreased OM; reduced the expression of CHOP, BIP, and caspase 3; and significantly decreased the proinflammatory gene expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These results suggest that PGPS triggers ER stress and downstream proinflammatory gene expression in OM and that inhibition of ER stress alleviates OM. We propose that ER stress plays a critical role in inflammation and cell death, leading to the development of OM and points to ER stress inhibition as a potential therapeutic approach for the prevention of OM.

/pdf/role-of-endoplasmic-reticulum-stress-in-otitis-media-2jfasy4s5b.pdf

Role of Endoplasmic Reticulum Stress in Otitis Media.

Hypopharyngeal and laryngeal neoplasms are both fatal and hard to catch in early stages. Yet which treatment is the most efficacious one still remain unanswered. This network meta-analysis (NMA) was conducted to investigate effectiveness of six therapies being utilized in clinical practice nowadays. PubMed and Embase were retrieved to synthesize data. Direct and indirect evidence was combined to compare efficacy of treatments. A relative ranking of the six regimens was calculated by the surface under the curve ranking area (SUCRA). A total of 28 trials with 9109 patients were included in our NMA. Five endpoints investigated included 3/5-year overall survival (3/5-OS), 3/5-year disease free survival (3/5-DFS) and 5-year overall survival rate (5-OSR). In terms of all efficacy outcomes, radiotherapy combined with surgery (RT + S) proved to be better than other therapies while radiotherapy (RT) alone also performed well. Induction chemoradiotherapy (ICRT) was the best regarding 3-DFS (SUCRA = 0.846) while current chemoradiotherapy (CCRT) ranked first in 5-DFS (SUCRA = 0.933) according to SUCRA results. No significant differences were demonstrated in 5-DFS and 5-OSR as shown in the results of NMA. RT combined with surgery turned out to be optimal therapy of all the outcomes while the efficacy of RT was relatively poorer in the treatment of patients with larynx stage III-IV and hypopharynx stage II-IV. Also, the good performance of CCRT and ICRT in terms of DFS made them as secondary recommended therapies. There is no significant difference between surgery and transoral laser microsurgery (TLM) alone.

/pdf/comparative-efficacy-of-six-therapies-for-hypopharyngeal-and-1ioid9s4ek.pdf

Comparative efficacy of six therapies for Hypopharyngeal and laryngeal neoplasms: a network meta-analysis.

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Role of Endoplasmic Reticulum Stress in Otitis Media.

Comparative efficacy of six therapies for Hypopharyngeal and laryngeal neoplasms: a network meta-analysis.