Human chemerin induces eryptosis at concentrations exceeding circulating levels

Introduction:Human chemerin is an adipokine that regulates chemotaxis,inflammation,and glucose metabolism.In addition,accumulating evidence suggests that chemerin promotes apoptosis,autophagy,and pyroptosis.However,there are no data on its impact on eryptosis.The current study aimed to analyze the effects of human active Glu^(21)-Ser^(157) chemerin on eryptosis in vitro.Materials and Methods:Human chemerin 0-2-10-50μg/mL was incubated for 24 h with human erythrocytes(hematocrit 0.4%)obtained from eight healthy individuals.Flow cytometry-based determination of phospholipid scrambling,reactive oxygen species(ROS)production,and intracellular Ca^(2+)levels was performed.To supplement data on ROS and Ca^(2+)signaling in chemerin-mediated eryptosis,incubation in the presence or absence of antioxidants vitamin C and N-acetylcysteine and Ca^(2+)-binding agent EGTA was carried out,respectively.Confocal microscopy-based techniques were used to detect reactive nitrogen species(RNS)generation,involvement of caspase-3 and caspase-8,as well as the state of lipid order in cell membranes of erythrocytes exposed to human Glu^(21)-Ser^(157) chemerin.Results:Our observations suggest that human Glu^(21)-Ser^(157) chemerin had no impact on eryptosis parameters at 2μg/mL.However,chemerin stimulated phosphatidylserine externalization,ROS production,and Ca^(2+)accumulation at higher concentrations suggesting activation of eryptosis.Ca^(2+)uptake turned out to be at least partly required for chemerin-mediated eryptosis.Chemerin-mediated erythrotoxicity was additionally mediated by RNS,caspase-3,and caspase-8.Moreover,Glu^(21)-Ser^(157) chemerin promoted reduction in the liquid-ordered phase of cell membranes in erythrocytes.Conclusions:The present study first discloses that human chemerin can induce eryptosis via Ca^(2+)-dependent mechanisms at concentrations noticeably exceeding circulating levels.Thus,chemerin-induced eryptosis can hardly contribute to eryptosis-mediated anemia in diseases associated with enhanced levels of chemerin in blood.

FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma

Objective:FGFR is considered an important driver gene of lung squamous cell carcinoma(LSCC).Thus,identification of the biological events downstream of FGFR is important for the treatment of this malignancy.Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells.However,the biological functions of the FGFR/RACK1 complex remain poorly understood.Methods:Anchorage-independent assays and in vivo tumorigenesis assays were performed to evaluate cancer cell malignancy.Distant seeding assays were performed to evaluate cancer cell metastasis.β-gal staining was used to examine cell senescence,and immunoprecipitation assays were performed to examine the interactions among FGFR,RACK1,and MDM2.Results:FGFR/RACK1 was found to regulate the senescence of LSCC cells.Treatment with PD166866,an inhibitor of FGFR,or knockdown of RACK1 induced senescence in LSCC cells(P<0.01).A molecular mechanistic study showed that FGFR/RACK1/MDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence.PD166866 and RG7112,an MDM2/p53 inhibitor,cooperatively inhibited the colony formation and distal seeding of LSCC cells(P<0.01),and upregulated the expression of p53 and p21.Conclusions:Together,our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence.This understanding should be important in the treatment of LSCC.

Heart failure in older adults：embracing complexity

Heart failure （HF）, particularly in the setting of preserved systolic function, disproportionately afflicts older individu- als and results in significant morbidity, mortality, and health care costs. In the United States, among the Medicare population （age 〉 65 years）, HF is among the leading cause of hospital admissions. Optimal care for older adults with HF requires knowledge of age-related physiologic changes, complex multi-organ, multi-dimensional syndromes, interdisciplinary teamwork and palliative/end of life care.

Syncope in older adults

Syncope, defined as a self-limited transient loss of con- sciousness and postural tone due to global cerebral hypoperfusion, is a common reason for emergency room visits, with a third of these visits leading to an inpatient admission.

Cardiovascular effects of hemoglobin response in patients receiving epoetin alfa and oral iron in heart failure with a preserved ejection fraction

Background Previous data from a recently conducted prospective, single blind randomized clinical trial among community dwelling older patients with heart failure with a preserved ejection fraction （HFPEF） and anemia randomized to treatment with epoetin alfa （erythro-poiesis-stimulating agents, ESA） vs. placebo did not demonstrate significant benefits of therapy regarding left ventricular （LV） structure, functional capacity, or quality of life （QOL）. However, several patients randomized to the treatment arm were non-responders with a subop-timal increase in hemoglobin. All patients in the trial also received oral ferrous gluconate, which could have contributed to increases in he-moglobin observed in those receiving placebo. Accordingly, we performed an analysis separating patients into responders vs. non-responders in order to determine if measured improvement in anemia would have any effect on clinical endpoints. Methods A total of 56 patients （age 77 ± 11 years, 68%female） were recruited who had anemia defined as a hemoglobin of≤12 g/dL （average, 10.4 ± 1 g/dL） with HFPEF defined as having NHANES-CHF （National Health And Nutrition Examination Survey：Congestive Heart Failure） criteria score of≥3 and an ejection fraction of＆gt;40%（average EF=63%±15%）. Patients were randomly allocated to receive either ESA and ferrous gluconate or ferrous gluconate only. In this analysis, a responder was defined as a patient with an increase of 1 g/dL in the first 4 weeks of the trial. Re-sults Nineteen subjects were classified as responders compared to 33 non-responders. While the average hemoglobin increased signifi-cantly at the end of 6 months for responders （1.8 ± 0.3 vs. 0.8 ± 0.2 g/dL, P = 0.004）, 50% of the subjects assigned to ESA were non-responders. Left ventricular function including ejection fraction （P=0.32） and end diastolic volume （P=0.59） was unchanged in res-ponders compared to non-responders. Responders also showed no significant improvements in New York Heart Association （NYHA） class, Six Minute Walk Test （6 MWT） and peak VO2. Though QOL improved significantly within each group, there was no difference between the two. Conclusions A significant hemoglobin response to anemia treatment with ESA and oral iron does not lead to differences in LV re-modeling, functional status, or QOL. Additionally, a significant percent of older adults with HFPEF and anemia do not respond to ESA ther-apy. Given the results of this small trial, it appears as though using objective improvements in anemia as a marker in older adult subjects with HFPEF does not have significant clinical utility.

Pain Hypersensitivity: A Bio-Psychological Explanation of Chronic Musculoskeletal Pain and Underpinning Theory

Hypersensitivity is a phenomenon that has a dual role: adaptive (protective) and maladaptive (pathological) based on different aspects of the pain mechanism. The mechanism of hypersensitivity has not been fully defined. However, it is known that over-excitability (too much sensitivity) of neurons can arise in both peripheral and central components of the nervous system. Pain theories can be useful in helping to explain complex phenomenon like hypersensitivity. The Gate control theory and other more bio-psychological pain models may assist us to understand a mechanism of chronic musculoskeletal pain. This article discusses a mechanism based pain model.