Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia

Chen, Mengxing; Yan, Rong; Zhou, Kangxi; Li, Xiaodong; Zhang, Yang; Liu, Chunliang; Jiang, Mengxiao; Ye, Honglei; Meng, Xiangjun; Pang, Ningbo; Zhao, Lili; Li, Jun; Xiao, Wenjin; Hu, Renping; Cui, Qingya; Zhong, Wei; Zhao, Yi; Zhu, Mingqing; Lin, Anning; Ruan, Changgeng; Dai, Kesheng

doi:10.1073/pnas.1808217115

Cited by 57 publications

(58 citation statements)

References 73 publications

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“…JC-1 assays measure Ψm depolarisation of the mitochondria membrane, and such depolarisation indicates active cell apoptosis and accelerated ageing. [59][60][61] Beego significantly reduced the percentage of JC-1 green fluorescence ( figure 4H), suggesting an increase mitochondrial in mitochondrial membrane potential and thus a reduction in intrinsic pathway triggered activation of apoptosis. Consistently, flow cytometry analysis of Annexin V levels revealed a detectable beego-induced reduction in the extent of platelet apoptosis ( figure 4I).…”

Section: Supervised Beego Reduces Platelet Counts But Retains Platelementioning

confidence: 94%

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

Fang

Zhao

et al. 2021

BMJNPH

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Beego is a traditional Chinese complete water-only fasting practice initially developed for spiritual purposes, later extending to physical fitness purposes. Beego notably includes a psychological induction component that includes meditation and abdominal breathing, light body exercise and ends with a specific gradual refeeding program before returning to a normal diet. Beego has regained its popularity in recent decades in China as a strategy for helping people in subhealthy conditions or with metabolic syndrome, but we are unaware of any studies examining the biological effects of this practice. To address this, we here performed a longitudinal study of beego comprising fasting (7 and 14 day cohorts) and a 7-day programmed refeeding phase. In addition to detecting improvements in cardiovascular physiology and selective reduction of blood pressure in hypertensive subjects, we observed that beego decreased blood triacylglycerol (TG) selectively in TG-high subjects and increased cholesterol in all subjects during fasting; however, the cholesterol levels were normalised after completion of the refeeding program. Strikingly, beego reduced platelet formation, activation, aggregation and degranulation, resulting in an alleviated thrombosis risk, yet maintained haemostasis by sustaining levels of coagulation factors and other haemostatic proteins. Mechanistically, we speculate that downregulation of G6B and MYL9 may influence the observed beego-mediated reduction in platelets. Fundamentally, our study supports that supervised beego reduces thrombosis risk without compromising haemostasis capacity. Moreover, our results support that beego under medical supervision can be implemented as non-invasive intervention for reducing thrombosis risk, and suggest several lines of intriguing inquiry for future studies about this fasting practice (http://www.chictr.org.cn/index.aspx, number, ChiCTR1900027451).

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Section: Supervised Beego Reduces Platelet Counts But Retains Platelementioning

confidence: 94%

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

Fang

Zhao

et al. 2021

BMJNPH

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“…In summary, we introduce the first description of platelet apoptosis in severe (ICU) COVID-19 patients, suggesting a strong link between platelet apoptosis and thrombosis. These data may indicate platelet apoptosis as a potential target of COVID-19 treatment as has been suggested for ARDS 39 and other platelet disorders 35,40 .…”

Section: Discussionmentioning

confidence: 66%

“…To exclude potential contribution of platelet hyperactive status in our cohort, we assessed the impact of patients’ sera on platelet apoptosis. Recent data showed that autoantibodies from patients with autoimmune thrombocytopenia (ITP) are able to induce platelet apoptosis 35 . The incubation of sera as well as from IgG fractions from severe COVID-19 patients with platelets from healthy donors induced significant changes in apoptosis markers including ΔΨm depolarization, increased cytosolic Ca 2+ concentration, caspase 9 cleavage, and finally PS externalization.…”

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 infection is associated with increased antibody-mediated platelet apoptosis

Althaus

Marini

Zlamal

et al. 2020

Preprint

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The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial, involving interplay between cellular and plasmatic elements of the hemostasis. We hypothesized that COVID-19 is accompanied by platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; non-COVID-19 ICU) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in ΔΨm depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

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“…Apoptosis is the active process of cell death regulated by genes through which aging and abnormal cells are cleared. 18 Treatment with HP induced apoptosis in human megakaryocyte Dami cells. Annexin V-FITC/PI double staining was used to label cells treated with HP for 0 h, 3 h, 6 h, and 9 h. Flow cytometry was used to detect apoptotic cells, revealing the apoptosis rate increased significantly at 3 h after HP exposure.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling

Lei

Tan

et al. 2021

OTT

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Objective: To investigate the role of Helicobacter pylori (HP) on the regulation of NF-κB/ IL-17 signaling, mechanisms underlying apoptosis in human megakaryocyte cell lines Dami. Methods: Firstly, the mouse model of immune thrombocytopenia (ITP) was established. Then, the mice were subjected to gastric perfusion with HP. Next, the changes in platelet and bone marrow megakaryocyte classification were assessed in each group. Human megakaryocyte Dami cells were treated with HP in vitro for 3, 6, or 9 h; and the rates of apoptosis in each group were then evaluated with flow cytometry. Fluorescent quantitative PCR and Western blotting were implemented for assessing the expression of Bcl-2 and Bax, which are related to apoptosis, and p65, which is associated with the NF-κB pathway. The expression of these proteins was also evaluated after treatment with PDTC, an inhibitor of the NF-κB pathway inhibitor. Results: In vivo, exogenous administration of HP was found to increase the optical density value for the anti-HP antibody in HP-infected BALB/c mice. Meanwhile, the platelet counts in the HP-infected ITP mice model were significantly reduced compared with non-infected ITP mice. In vitro, the apoptotic rate of Dami cells increased gradually with the prolongation of the exposure to HP; the most noticeable change was at 6 h, and there was a significant difference between 0 h and 6 h. The expression of Bax, p-p65, and IL-17 also increased progressively with the prolongation HP exposure, while the expression of anti-apoptotic Bcl-2 protein decreased gradually, especially at 6 h, and the expression of total p65 did not change significantly compared with baseline. Anecdotally, these effects were reversed by the application of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling. Conclusion: HP can promote platelet destruction in ITP mice, and the underlying mechanisms may be related to accelerating apoptosis of megakaryocytes by the activation of the NF-κB/IL-17 pathway.

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Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia

Cited by 57 publications

References 73 publications

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

Severe COVID-19 infection is associated with increased antibody-mediated platelet apoptosis

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling

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