The devastating coronavirus disease of 2019 (COVID-2019) epidemic has been declared a public health emergency, resulting in a worldwide pandemic. The omicron variety is the most common epidemic mutant strain in the globe. Serum beta-2 microglobulin (β2-MG) is associated with endothelial cell injury and has value in monitoring the progression of inflammation in infected individuals. Nonetheless, the potential functions of β2-MG in omicron remain elusive.To investigate the prognostic value of serum β2-MG levels at diagnosis, we retrospectively analyzed a cohort of 240 people with omicron. Over the course of 65 days, all patients were monitored, and death was the primary outcome. Patients were allocated to two groups: those with high and low β2-MG levels. The Kaplan-Meier method was used to examine OS, and the log-rank test was used to compare them. Univariate and multivariate Cox hazard models were used to determine the prognostic significance.Our results revealed that β2-MG was significantly elevated in omicron. β2-MG levels in severe patients were higher than in mild-to-moderate patients, and the difference was statistically significant. Timely, interleukin-6 (IL-6) and interleukin-10 (IL-10) were observed to be significantly increased in individuals exhibiting elevated levels of β2-MG. In addition, patients exhibiting elevated levels of β2-MG demonstrated a statistically significant decrease in overall survival (OS, P < 0.0001). An elevated β2-MG level (≥4.72 mg/l) was found to be an independent, adverse prognostic factor for OS in omicron patients, according to multivariate Cox proportional hazards regression analysis (P = 0.001).Serum β2-MG level at initial diagnosis was significantly correlated with omicron severity and prognosis. Thus, we propose that β2-MG may be an independent poor additional prognostic factor in patients with omicron.
Lactate is critical in modeling tumor microenvironment causing chemotherapy resistance; however, the role of lactate in tyrosine kinase inhibitor (TKI) resistance has not been fully known. The aim of this study was to evaluate whether lactate could mediate TKI resistance through GPR81 and MCT1 in non-small-cell lung cancer (NSCLC). Here, we showed that lactate enhanced the cell viability and restrained erlotinib-induced apoptosis in PC9 and HCC827 cells. GPR81 and AKT expression were significantly increased with the addition of lactate, and siGPR81 reduced AKT expression resulting in a raised apoptosis rate with erlotinib treatment. Furthermore, we found that lactate also promoted MCT1 exposure, and inhibiting MCT1 with AZD3965 markedly impaired the glycolytic capacity. A significant increase of GPR81 and MCT1 expression was observed in insensitive tissues compared with sensitive ones by immunostaining in NSCLC patients. Our results indicate that lactate adopts dual strategies to promote TKI resistance in NSCLC, not only activating AKT signaling by GPR81, but also giving energy supply through MCT1-mediated input. Targeting GPR81 and MCT1 may provide new therapeutic modalities for TKI resistance in NSCLC.
Abstract Despite the high efficacy and safety of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) and eradicating APL leukemia-initiating cells (LICs), the mechanism underlying its selective cytotoxicity remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, through autophagy. However, the role of ETosis in ATO-induced APL LIC eradication remains unclear. For this study, we evaluated the effects of ATO on ETosis and the contributions of drug-induced ETosis to APL LIC eradication. In NB4 cells, ATO primarily increased ETosis at moderate concentrations (0.5–0.75 μM) and stimulated apoptosis at higher doses (1.0–2.0 μM). Furthermore, ATO induced ETosis through mammalian target of rapamycin (mTOR)-dependent autophagy, which was partially regulated by reactive oxygen species. Additionally, rapamycin-enhanced ATO-induced ETosis in NB4 cells and APL cells from newly diagnosed and relapsed patients. In contrast, rapamycin had no effect on apoptosis in these cells. We also noted that PML/RARA oncoprotein was effectively cleared with this combination. Intriguingly, activation of autophagy with rapamycin-enhanced APL LIC eradication clearance by ATO in vitro and in a xenograft APL model, while inhibition of autophagy spared clonogenic cells. Our current results show that ATO exerts antileukemic effects at least partially through ETosis and targets LICs primarily through ETosis. Addition of drugs that target the ETotic pathway could be a promising therapeutic strategy to further eradicate LICs and reduce relapse.
Paeonia lactiflora with the action of promoting blood circulation and removing blood stasis had been shown to be able to inhibit thrombosis and platelet aggregation, increase fibrinolytic activity and promote thrombolysis. This paper described the influence of the extract of Paeonia lactiflora in vitro experiments on prothrombin time (PT), activated partial thromboplastin time (PTT), antithrombin effect, activity of plasminogen and urokinase. The experimental results showed that: (1) The extract of Paeonia lactiflora prolonged the time of PT and PTT. (2) The extract of drug was able significantly to inhibit the thrombin. (3) In study of fibrinolysis by fibrin standard plate experiments, the drug possessed activative effect on the plasminogen. (4) The activity of urokinase was reduced, while the extract of Paeonia lactiflora existed. The inhibitory effect on thrombin and effective effect on plasminogen of the drug might be an important mechanism of its action of promoting blood circulation and removing blood stasis.
Background Essential thrombocythemia (ET) is characterized by thrombocytosis with increased platelet number and persistent activation. The mechanisms of thrombosis and the fate of these platelets are not clear. The aim of the present study is to explore the phagocytosis of platelets of ET patients by endothelial cells (ECs) in vitro and its relevance to the procoagulant activity (PCA). Methods Phosphatidylserine (PS) exposure on platelets was detected by flow cytometry. Phagocytosis of the platelets by ECs was performed using flow cytometry, confocal microscopy, and electron microscopy. The PCA of platelets was evaluated by coagulation time and purified coagulation complex assays. Results The PS exposure on platelets in ET patients is higher than that in healthy controls. The PS-exposed platelets are highly procoagulant and lactadherin reduced 80% of the PCA by blockade of PS. When cocultured, the platelets of ET patients were sequestered by ECs in a time-dependent fashion. Lactadherin enhanced phagocytosis by bridging the PS on activated platelets and the integrin αvβ3 on ECs, and P-selectin played at least a partial role in this process. Furthermore, factor Xa and prothrombinase activity of PS-exposed platelets were decreased after incubation with ECs. Conclusion Our results suggest that phagocytic clearance of platelets by ECs occurs in ET patients, thus representing a novel mechanism to remove activated platelets from the circulation; lactadherin and phagocytosis could cooperatively limit the thrombophilia in ET patients.
Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD.In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays.We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype.NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.
Abstract Aims Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. Methods As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients’ blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. Results A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients’ neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. Conclusions NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS.
Lactate, a marker of tumor metabolic reprogramming, maintains the acidic microenvironment and also affects the metabolism and function of immune cells. SLC16A3 is responsible for the extracellular transport of lactate, which is a key component of glycolysis. However, the role of SLC16A3 in immune infiltration and immunosuppression of lung cancer is largely unknown. Our study explored the therapeutic and prognostic value of SLC16A3 in predicting immune infiltration and immune checkpoint efficacy of lung cancer.SLC16A3 expression was evaluated with TCGA database. Kaplan-Meier analysis was performed for survival rates. GO and KEEG enrichment was conducted to determine predictive signaling pathways. We utilized TIMER and CIBERSORT to analyze the correlation between SLC16A3 and immunocyte infiltration as well as immune checkpoint. Interleukin and HIF-1a expression was measured with ELISA kit and flow cytometry separately.In comparison with normal tissues, SLC16A3 expression was significantly upregulated in both lung adenocarcinoma (LUAD) and squamous carcinoma (LUSC), which was closely related to poor prognosis. GO analysis indicated that SLC16A3 involved in different signal pathways in LUAD and LUSC and linked to HIF-1 signaling in LUAD. High SLC16A3 was correlated with immunosuppressive cells (Treg, Th2 and iDC), immune checkpoint (PD1, PD-L1, PVR, Tim-3, ITGAM) and immunosuppressive factors (foxp3, TGF-β) in LUAD not LUSC. Furthermore, SLC16A3 was identified to tightly interact with IL-8 which may induce microenvironment immune tolerance. Based on the clinical prediction, we performed experiments with LUAD A549 cells and showed reduced IL-8 and HIF-1a when treated with SLC16A3 knockdown. HIF-1a stimulation by dimethyloxalylglycine (DMOG) could restore IL-8 secretion in SLC16A3 downregulated cells.Taken together, our results suggest that SLC16A3 contributes to a worse prognosis in lung cancer and may play an important role in immune microenvironment and evasion through HIF-1a-IL8 axis, which could be a novel therapeutic target for immunotherapy in lung cancer.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)