Amyloid in neurodegenerative diseases: Friend or foe?

Accumulation of amyloid-like aggregates is a hallmark of numerous neurodegenerative disorders such as Alzheimer’s and polyglutamine disease. Yet, whether the amyloid inclusions found in these diseases are toxic or cytoprotective remains unclear. Various studies suggest that the toxic culprit in the amyloid folding pathway is actually a soluble oligomeric species which might interfere with normal cellular function by a multifactorial mechanism including aberrant protein-protein interactions. Molecular chaperones suppress toxicity of amyloidogenic proteins by inhibiting aggregation of non-native disease substrates and targeting them for refolding or degradation. Paradoxically, recent studies also suggest a protective action of chaperones in their promotion of the assembly of large, tightly packed, benign aggregates that sequester toxic protein species

Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research

The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins

Escape of aberrant proteins from protein quality control leads to accumulation of toxic protein species. Sti1 interacts with Hsp70 to mediate spatial PQC of amyloid-like proteins by regulating their distribution in different intracellular protein-handling depots. Sti1 suppresses proteotoxicity by targeting amyloid-like proteins to perinuclear foci.Conformational diseases are associated with the conversion of normal proteins into aggregation-prone toxic conformers with structures similar to that of β-amyloid. Spatial distribution of amyloid-like proteins into intracellular quality control centers can be beneficial, but cellular mechanisms for protective aggregation remain unclear. We used a high-copy suppressor screen in yeast to identify roles for the Hsp70 system in spatial organization of toxic polyglutamine-expanded Huntingtin (Huntingtin with 103Q glutamine stretch [Htt103Q]) into benign assemblies. Under toxic conditions, Htt103Q accumulates in unassembled states and speckled cytosolic foci. Subtle modulation of Sti1 activity reciprocally affects Htt toxicity and the packaging of Htt103Q into foci. Loss of Sti1 exacerbates Htt toxicity and hinders foci formation, whereas elevation of Sti1 suppresses Htt toxicity while organizing small Htt103Q foci into larger assemblies. Sti1 also suppresses cytotoxicity of the glutamine-rich yeast prion [RNQ+] while reorganizing speckled Rnq1–monomeric red fluorescent protein into distinct foci. Sti1-inducible foci are perinuclear and contain proteins that are bound by the amyloid indicator dye thioflavin-T. Sti1 is an Hsp70 cochaperone that regulates the spatial organization of amyloid-like proteins in the cytosol and thereby buffers proteotoxicity caused by amyloid-like proteins

Bacteria-Specific Neutrophil Dysfunction Associated with Interferon-Stimulated Gene Expression in the Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a poorly understood condition with greater than 30% mortality. Massive recruitment of neutrophils to the lung occurs in the initial stages of the ARDS. Significant variability in the severity and duration of ARDS-associated pulmonary inflammation could be linked to heterogeneity in the inflammatory capacity of neutrophils. Interferon-stimulated genes (ISGs) are a broad gene family induced by Type I interferons. While ISGs are central to anti-viral immunity, the potential exists for these genes to evoke extensive modification in cellular response in other clinical settings. In this prospective study, we sought to determine if ISG expression in circulating neutrophils from ARDS patients is associated with changes in neutrophil function. Circulating neutrophil RNA was isolated, and hierarchical clustering ranked patients' expression of three ISGs. Neutrophil response to pathogenic bacteria was compared between normal and high ISG-expressing neutrophils. High neutrophil ISG expression was found in 25 of 95 (26%) of ARDS patients and was associated with reduced migration toward interleukin-8, and altered responses to Staphylococcus aureus, but not Pseudomonas aeruginosa, which included decreased p38 MAP kinase phosphorylation, superoxide anion release, interleukin-8 release, and a shift from necrotic to apoptotic cell death. These alterations in response were reflected in a decreased capacity to kill S. aureus, but not P. aeruginosa. Therefore, the ISG expression signature is associated with an altered circulating neutrophil response phenotype in ARDS that may predispose a large subgroup of patients to increased risk of specific bacterial infections

Feasibility study to assess the delivery of a novel isometric exercise intervention for people with stage 1 hypertension in the NHS: protocol for the IsoFIT-BP study including amendments to mitigate the risk of COVID-19.

BackgroundHypertension  (HTN) affects approximately 25% of the UK population and is a leading cause of mortality. Associated annual health care costs run into billions. National treatment guidance includes initial lifestyle advice, followed by anti-hypertensive medication if blood pressure (BP) remains high. However, adoption and adherence to recommended exercise guidelines, dietary advice and anti-hypertensive medication is poor. Four short bouts of isometric exercise (IE) performed 3 days per week (d/wk) at home elicits clinically significant reductions in BP in those with normal to high-normal BP. This study will determine the feasibility of delivering personalised IE to patients with stage 1 hypertension for whom lifestyle changes would be recommended before medication within NHS primary care.MethodsThis is a randomised controlled feasibility study. Participants were 18+ years, with stage 1 hypertension, not on anti-hypertensive medication and without significant medical contraindications. Trial arms will be standard lifestyle advice (control) or isometric wall squat exercise and standard lifestyle advice. Primary outcomes include the feasibility of healthcare professionals to deliver isometric exercise prescriptions in a primary care NHS setting and estimation of the variance of change in systolic BP. Secondary outcomes include accuracy of protocol delivery, execution of and adherence to protocol, recruitment rate, attrition, perception of intervention viability, cost, participant experience and accuracy of home BP. The study will last 18 months. Sample size of 100 participants (50 per arm) allows for 20% attrition and 6.5% incomplete data, based upon 74 (37 each arm) participants (two-sided 95% confidence interval, width of 1.33 and standard deviation of 4) completing 4 weeks. Ethical approval IRAS ID is 274676.DiscussionBefore the efficacy of this novel intervention to treat stage 1 hypertension can be investigated in any large randomised controlled trial, it is necessary to ascertain if it can be delivered and carried out in a NHS primary care setting. Findings could support IE viability as a prophylactic/alternative treatment option.Trial registrationISRCTN13472393 , registered 18 August 2020