Effect of KIR/HLA receptor-ligand mode on prognosis of single unrelated cord blood transplantation in patients with hematological malignancies / 中华血液学杂志

Objective: To explore the impact of the natural killer cell immunoglobulin-like receptor/human leukocyte antigen (KIR/HLA) receptor-ligand model in single unrelated cord blood transplantation (sUCBT) . Methods: Between July 2012 and June 2018, 270 patients with malignant hematologic diseases receiving single-unit UCBT were divided into two groups. Group 1 (n=174) patients lacked a C-ligand for inhibitory KIR on UCB NK cells (patients homozygous C1/C1 or C2/C2) . Group 2 (n=96) patients expressed both C ligands for inhibitory KIR in the receptor (patients heterozygous C1/C2) . Results: A total of 270 patients (146 males, 124 females) with a median age of 13 years (1-62) were included in this retrospective study. All patients received a myeloablative conditioning regimen (without ATG) . The ratio of neutrophil engraftment for group 1 and 2 were both 98.9%, the median time of neutrophil engraftment for group 1 and 2 was 16 (10-41) days vs 17 (11-33) days (P=0.705) . The ratio of platelet engraftment was 88.5% for group 1 and 87.5% for group 2, the median time of platelet engraftment was 35 (11-113) days vs 38.5 (13-96) days (P=0.317) . The cumulative incidence of Ⅱ-Ⅳ acute GVHD in 100 days was 38.7% (95%CI 31.4%-45.9%) for group 1 and 50.0% (95%CI 39.6%-59.6%) for group 2 (P=0.075) , but multivariate analysis showed that HLA-C ligand absence was an independent protective factor for Ⅱ-Ⅳ acute GVHD after transplantation (P=0.036) . Patients in absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower relapse rate than patients with both C-ligands (group 2) : 17.7% (95%CI 11.7%-24.9%) vs 22.7% (95%CI 4.4%-32.2%) after 3 years (P=0.288) . The median follow-up time was 742 (335-2 512) days. The 3-year OS was 72.1% for group 1 and 60.5% for group 2 (P=0.079) . There was no statistically significant difference between the two groups in 3-year disease-free survival [64.9% (95%CI 56.2%-72.3%) vs 55.4% (95%CI 44.4%-65.0%) (χ(2)=3.027, P=0.082) ]. Non-relapse mortality for group 1 was 12.1% (95%CI 7.7%-17.4%) and for group 2 was 16.7% (95%CI 10.0%-24.8%) (P=0.328) . Conclusion: Patients lacking a KIR-ligand of HLA group C1 or C2 had a lower incidence of grades Ⅱ-Ⅳ acute GVHD after sUCBT.

Effects of high glucose induced primary cardiomyocytes injury on necroptosis and the related mechanism / 中国应用生理学杂志

OBJECTIVE@#To observe whether necroptosis was happened in high glucose (HG) - induced primary cardiomyocytes injury and to investigate the likely mechanism.@*METHODS@#The primary cultured cardiomyocytes were divided into 4 groups (n=9): control group (the cardiomyocytes were incubated with 5.5 mmol/L glucose for 48 h), HG group (the cardiomyocytes were incubated with 30 mmol/L glucose for 48 h), HG + necrostatin-1 (Nec-1) group (the cardiomyocytes was co-incubated with necroptosis inhibitor Nec-1 at 100 μmol/L and HG for 48 h) and hypertonic pressure group (HPG, the cardiomyocytes was co-incubated with 5.5 mmol/L glucose and 24.5 mmol/L mannitol for 48 h). Cell viability was measured by MTT method, reactive oxygen species (ROS) generation was measured by DHE staining. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were tested by ELISA method. The mRNA and protein expressions of necroptosis related genes receptor interacting serine/threonine protein kinase 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL) were tested by quantitative real-time PCR and Western blot.@*RESULTS@#The results showed HG intervention decreased cardiomyocytes viability, increased ROS generation, up-regulated the levels of TNF-α, IL-6 and IL-1β, increased RIP1, RIP3, MLKL expressions at mRNA and protein levels. Nec-1 treatment attenuated HG-induced increased cardiomyocytes viability, reduced ROS generation, down-regulated the levels of TNF-α, IL-6 and IL-1β, decreased RIP1, RIP3, MLKL expressions at mRNA and protein levels.@*CONCLUSION@#Necroptosis was happened in high glucose-induced primary cardiomyocytes injury. Inhibition of necroptosis can reduce high glucose-induced cardiomyocytes damage, may be related to inhibition of oxidative stress and depression of inflammative factors releasing.

Effects of activation of mitochondrial aldehyde dehydrogenase 2 on MMP-14 and TIMP-4 in high glucose induced rat cardiomyocytes injury / 中国药理学通报

Aim To observe whether matrix metallo-proteinase-14 ( MMP-14) and tissue matrix metallopro-teinase inhibitor-4 ( TIMP-4) were involved in the car-diac-protection of mitochondrial aldehyde dehydrogen-ase 2 ( ALDH2) against high glucose induced rat pri-mary cardiomyocyte injury. Methods Rat primary cardiomyocytes were cultured. The cardiomyocyte via-bility was detected by MTT assay at different concentra-tion of glucose at different time point. After established high glucose-induced cardiomyocytes injury model, cardiomyocytes were randomly divided into 4 groups:normal control group ( NG, glucose at 5.5 mmol· L-1) , NG + Alda-1 group ( Alda-1 at 20 μmol·L-1) , high glucose group ( HG, glucose at 30 mmol·L-1) and HG+Alda-1 group. The cell viability at 48 h and oxidative stress level were detected by MTT and DHE staining methods. The protein expressions of ALDH2, MMP-14 and TIMP-4 were determined by Western blot. Results The cardiomyocytes injury model was established according to the cell activity result. Com-pared with NG group, the cell viability, the protein ex-pressions of ALDH2, MMP-14, the ratio of MMP-14/TIMP-4 were decreased, TIMP-4 protein expression and the level of oxidative stress were increased in HG group. Compared with HG group, in HG + Alda-1 group, the cell viability, the protein expressions of AL-DH2, MMP-14, the ratio of MMP-14/TIMP-4 were in-creased, the levels of oxidative stress and TIMP-4 pro-tein expression were decreased. Conclusion Activa-tion of mitochondrial ALDH2 may relieve high glucose induced cardiomyocytes injury. The protective effect was likely related to the inhibition of oxidative damage, down-regulation of MMP-14 and up-regulation of TIMP-4 proteins.

Role of autophagy in fasudil-induced Rho kinase inhibition for protection against myocardial ischemia-reperfusion injury in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes of autophagy in ischemic myocardium of rats treated with fasudil for inhibiting Rho kinase.</p><p><b>METHODS</b>The hearts isolated from male Sprague-Dawley rats were subjected to 30 min of occlusion of the left anterior descending artery followed by 120 min of reperfusion with or without treatment with fasudil or fasudil+Wort. The left ventricular hemodynamics were continuously recorded, and the coronary effluent was collected during the reperfusion to determine lactate dehydrogenase (LDH) levels. The mRNA expressions of autophagy-related genes Atg5 and Beclin1 and apoptosis-related genes bax and bcl-2 were detected by RT-PCR, and the protein expression of caspase-3 was detected by Western blotting.</p><p><b>RESULTS</b>Compared with I/R group, fasudil significantly improved the left ventricular developed pressure, maximal rise/fall rate of left ventricular pressure and rate pressure product, reduced LDH release during reperfusion, increased Atg5 and Beclin1 mRNA expression and the ratio of Bcl-2/Bax, and lowered caspase 3 protein expression. The autophagy inhibitor Wort significantly attenuated the effect of fasudil in the rat hearts.</p><p><b>CONCLUSION</b>Fasudil treatment for inhibiting Rho kinase promoted autophagy in ex vivo rat heart to protect against myocardial ischima-reperfusion injury possibly by reducing apoptosis of the cardiac myocytes.</p>