Moxifloxacin Disrupts and Attenuates Aß42 Fibril and Oligomer Formation: Plausibly Repositioning an Antibiotic as Therapeutic against Alzheimer's Disease.

The aggregation of Aß42 is established as a key factor in the development of Alzheimer's disease (AD). Consequently, molecules that inhibit aggregation of peptide may lead to therapies to prevent or control AD. Several studies suggest that oligomeric intermediates present during aggregation may be more cytotoxic than fibrils themselves. In this work, we examine the inhibitory activity of an antibiotic MXF on aggregation (fibrils and oligomers) and disaggregation of Aß42 using various biophysical and microscopic studies. Computational analysis was done to offer mechanistic insight. The amyloid formation of Aß42 is suppressed by MXF, as demonstrated by the decrease in both the corresponding ThT fluorescence intensity and other biophysical techniques. The lag phase of amyloid formation doubled from 4.53 to 9.66 h in the presence of MXF. The addition of MXF at the completion of the fibrillation reaction, as monitored by ThT, led to a rapid, concentration dependent, exponential decrease in fluorescence signal that was consistent with loss of fibrils. We used TEM to directly demonstrate that MXF caused fibrils to disassemble. Our docking results show that MXF binds to both monomeric and fibrillar forms of Aß42 with significant affinities. We also observed breaking of fibrils in the presence of MXF through molecular dynamics simulation. These findings suggest that antibiotic MXF could be a promising lead compound with dual role as fibril/oligomer inhibitor and disaggregase for further development as potential repurposed therapeutic against AD.

Prognostic Interplay Between Coronary Artery Calcium Scoring and Cardiorespiratory FItness: The CAC-FIT Study.

OBJECTIVE: To assess the incremental prognostic role of coronary artery calcium score (CACS) and exercise capacity (EC), two independent prognostic tests in the assessment of patients with coronary artery disease. METHODS: The cohort consisted of patients who had clinically indicated exercise stress testing and CACS assessment from January 1, 2015, to September 30, 2021, with a median of 27 days between each other. Exercise capacity was defined by peak metabolic equivalents of task (METs) achieved during exercise stress test. The CACS was determined by the Agatston method. Patients were observed from the latest test date to incident major adverse cardiac events (inclusive of all-cause death, nonfatal myocardial infarction, late revascularization, and admission for heart failure). RESULTS: There were a` total of 1932 patients in the study population (mean age, 56±12 years; 42% female, 48% hypertension, 21% diabetes, 48% dyslipidemia). Peak METs below 6 was achieved in 8% of patients, and the median (interquartile range) CACS was 9 (0-203). In multivariable Cox regression models, both CACS (1 unit increase in log CACS: hazard ratio, 1.19; 95% CI, 1.06 to 1.34; P=.003;) and EC (1 unit increase in peak METs: hazard ratio, 0.89; 95% CI, 0.81 to 0.97; P=.01) were independently associated with outcomes. Using CACS+EC added incremental prognostic value over clinical and fitness models (C index increase from 0.68 to 0.75; P=.015). Incident event rates increased across categories of CACS and EC. CONCLUSION: Our analysis found that CACS and EC have complementary risk-stratifying roles in coronary artery disease.

The inhibitory effect of Sunset Yellow on thermally induced Human Serum Albumin aggregates: Possible role in naturopathy.

Intensive research in the field of protein aggregation confirmed that the deposition of amyloid fibrils of proteins are the major cause for the development of various neurotoxic and neurodegenerative diseases, which could be controlled by ensuring the efficient inhibition of aggregation using anti aggregation strategies. Herein, we elaborated the anti amyloidogenic potential of Sunset Yellow (SY) dye against Human Serum Albumin (HSA) fibrillogenesis utilising different biophysical, computational and microscopic techniques. The inhibitory effect of sunset yellow was confirmed by Rayleigh Light Scattering (RLS) measurements along with different dye binding assays (ANS, ThT and CR) by showing concentration dependent reduction in scattering intensity and fluorescence intensity respectively. Further, destabilization and anti fibrillation activity of HSA aggregates were characterized through spectroscopic techniques like Circular Dichroism (CD) and other microscopic techniques like Transmission Electron Microscopy (TEM) for elucidating the structural properties. The SDS-PAGE was also carried out that render the disaggregation effect of the dye on the protein. Moreover, Molecular Docking studies revealed the binding parameters justifying the stable protein-dye complex. Simulation studies were also performed accordingly. Thus, this dye which is used as food additive can serve as a potential aggregation inhibiting agent that can aid in the prevention of amyloidogenic diseases.

The coronary artery calcium score and stress myocardial perfusion imaging provide independent and complementary prediction of cardiac risk.

OBJECTIVES: This study sought to examine the relationship between coronary artery calcium score (CACS) and single-photon emission computed tomography (SPECT) results for predicting the short- and long-term risk of cardiac events. BACKGROUND: The CACS and SPECT results both provide important prognostic information. It is unclear whether integrating these tests will better predict patient outcome. METHODS: We followed-up 1,126 generally asymptomatic subjects without previous cardiovascular disease who had a CACS and stress SPECT scan performed within a close time period (median 56 days). The median follow-up was 6.9 years. End points analyzed were total cardiac events and all-cause death/myocardial infarction (MI). RESULTS: An abnormal SPECT result increased with increasing CACS from <1% (CACS < or =10) to 29% (CACS >400) (p < 0.001). Total cardiac events and death/MI also increased with increasing CACS and abnormal SPECT results (p < 0.001). In subjects with a normal SPECT result, CACS added incremental prognostic information, with a 3.55-fold relative increase for any cardiac event (2.75-fold for death/MI) when the CACS was severe (>400) versus minimal (< or =10). Separation of the survival curves occurred at 3 years after initial testing for all cardiac events and at 5 years for death/MI. CONCLUSIONS: The CACS and SPECT findings are independent and complementary predictors of short- and long-term cardiac events. Despite a normal SPECT result, a severe CACS identifies subjects at high long-term cardiac risk. After a normal SPECT result, our findings support performing a CACS in patients who are at intermediate or high clinical risk for coronary artery disease to better define those who will have a high long-term risk for adverse cardiac events.