A Preliminary Study of Mild Heat Stress on Inflammasome Activation in Murine Macrophages.

Inflammation and mitochondrial-dependent oxidative stress are interrelated processes implicated in multiple neuroinflammatory disorders, including Alzheimer's disease (AD) and depression. Exposure to elevated temperature (hyperthermia) is proposed as a non-pharmacological, anti-inflammatory treatment for these disorders; however, the underlying mechanisms are not fully understood. Here we asked if the inflammasome, a protein complex essential for orchestrating the inflammatory response and linked to mitochondrial stress, might be modulated by elevated temperatures. To test this, in preliminary studies, immortalized bone-marrow-derived murine macrophages (iBMM) were primed with inflammatory stimuli, exposed to a range of temperatures (37-41.5 °C), and examined for markers of inflammasome and mitochondrial activity. We found that exposure to mild heat stress (39 °C for 15 min) rapidly inhibited iBMM inflammasome activity. Furthermore, heat exposure led to decreased ASC speck formation and increased numbers of polarized mitochondria. These results suggest that mild hyperthermia inhibits inflammasome activity in the iBMM, limiting potentially harmful inflammation and mitigating mitochondrial stress. Our findings suggest an additional potential mechanism by which hyperthermia may exert its beneficial effects on inflammatory diseases.

Risk Factors and Outcomes in Critically Ill Patients with Hematological Malignancies Complicated by Hospital-Acquired Infections.

Background and objectives: Patients admitted to the intensive care unit (ICU) have an increased risk of hospital-acquired infection (HAI). A diagnosis of cancer alone increases the risk of sepsis three-five-fold, which further increases the risk of nosocomial infection, subsequently deteriorates results, and leads to high mortality. In this study, we aimed to assess the mortality rate among hematologic oncologic patients with suspected infection who were subsequently admitted to the ICU and the predictive factors that are associated with high ICU mortality. Materials and Methods: This retrospective cohort study was conducted in the hematological oncology critical care unit of a tertiary care hospital between November 2017 and February 2021. We analyzed anonymized medical records of hospitalized hematologic oncologic patients who were suspected or proven to have infection in the hematology-oncology department and were subsequently transferred to the ICU. Results: Both shorter hospitalization and shorter ICU stay length were observed in survivors [9.2 (7.7-10.4)] vs. non-survivors [10 (9.1-12.9), p = 0.004]. Sepsis had the highest hazard ratio (7.38) among all other factors, as patients with sepsis had higher mortality rates (98% among ICU non-survivors and 57% among ICU survivors) than those who had febrile neutropenia. Conclusions: The overall ICU mortality in patients with hematologic malignancies was 66%. Sepsis had the highest hazard ratio among all other predictive factors, as patients with sepsis had higher mortality rates than those who had febrile neutropenia. Chronic hepatitis (HBV and HCV) was significantly associated with higher ICU mortality.

Nuclear matrix metalloproteinases: functions resemble the evolution from the intracellular to the extracellular compartment.

Matrix metalloproteinase (MMP) is defined as an endopeptidase in the extracellular matrix (ECM), which plays essential roles in physiological processes such as organogenesis, wound healing, angiogenesis, apoptosis and motility. MMPs are produced and assembled in the cytoplasm as proenzymes with a cytoplasmic domain and require extracellular activation. MMPs can degrade receptors, extracellular matrix proteins, PARPs and release apoptotic substances. MMPs have been found in the cytosol, organelles and extracellular compartments and recently many types of MMPs have been found in the nucleus. However, the mechanisms and roles of MMPs inside the cell nucleus are still poorly understood. Here we summarized the nuclear localization mechanisms of MMPs and their functions in the nucleus such as apoptosis, tissue remodeling upon injury and cancer progression. Most importantly, we found that nuclear MMPs have evolved to translocate to membrane and target ECM possibly through evolution of nuclear localization signal (NLS), natural selection and anti-apoptotic survival. Thus, the knowledge about the evolution and regulation of nuclear MMPs appears to be essential in understanding a variety of cellular processes along with the development of MMP-targeted therapeutic drugs against the progression of certain diseases.