In both cardiomyocytes and HeLa cells, hypoxia (1% O(2)) quickly leads to microtubule disruption, but little is known about how microtubule dynamics change during the early stages of hypoxia. We demonstrate that microtubule associated protein 4 (MAP4) phosphorylation increases while oncoprotein 18/stathmin (Op18) phosphorylation decreases after hypoxia, but their protein levels do not change. p38/MAPK activity increases quickly after hypoxia concomitant with MAP4 phosphorylation, and the activated p38/MAPK signaling leads to MAP4 phosphorylation and to Op18 dephosphorylation, both of which induce microtubule disruption. We confirmed the interaction between phospho-p38 and MAP4 using immunoprecipitation and found that SB203580, a p38/MAPK inhibitor, increases and MKK6(Glu) overexpression decreases hypoxic cell viability. Our results demonstrate that hypoxia induces microtubule depolymerization and decreased cell viability via the activation of the p38/MAPK signaling pathway and changes the phosphorylation levels of its downstream effectors, MAP4 and Op18.

BackgroundPreeclampsia (PE) is an obstetric disorder with high morbidity and mortality rates but without clear pathogeny. The dysfunction of the blood coagulation-fibrinolysis system is a salient characteristic of PE that varies in severity, and necessitates different treatments. Therefore, it is necessary to find suitable predictors for the onset and severity of PE.ObjectivesWe aimed to evaluate blood coagulation parameters and platelet indices as potential predictors for the onset and severity of PE.MethodsBlood samples from 3 groups of subjects, normal pregnant women (n = 79), mild preeclampsia (mPE) (n = 53) and severe preeclampsia (sPE) (n = 42), were collected during early and late pregnancy. The levels of coagulative parameters and platelet indices were measured and compared among the groups. The receiver-operating characteristic (ROC) curves of these indices were generated, and the area under the curve (AUC) was calculated. The predictive values of the selected potential parameters were examined in binary regression analysis.ResultsDuring late pregnancy in the normal pregnancy group, the activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and platelet count decreased, while the fibrinogen level and mean platelet volume (MPV) increased compared to early pregnancy (p<0.05). However, the PE patients presented with increased APTT, TT, MPV and D-dimer (DD) during the third trimester. In the analysis of subjects with and without PE, TT showed the largest AUC (0.743) and high predictive value. In PE patients with different severities, MPV showed the largest AUC (0.671) and ideal predictive efficiency.ConclusionNormal pregnancy causes a maternal physiological hypercoagulable state in late pregnancy. PE may trigger complex disorders in the endogenous coagulative pathways and consume platelets and FIB, subsequently activating thrombopoiesis and fibrinolysis. Thrombin time and MPV may serve as early monitoring markers for the onset and severity of PE, respectively.

Hypoxic or ischemic apoptosis is often tightly associated with the opening of mitochondrial permeability transition pore (mPTP); however, the molecular mechanisms regulating mPTP and thus mitochondrial-dependent apoptosis remain elusive. Emerging evidence indicates that the movement of key proteins in or out of mitochondria play a critical regulatory role in apoptosis. Here, we reported that, unexpectedly, the microtubule-associated protein 4 (MAP4) translocated from cytosol to mitochondria upon phosphorylation after hypoxia treatment in neonatal cardiomyocytes. When targeted to mitochondria, MAP4 was found to lead to mPTP opening and induce apoptosis. Mitochondrial accumulation and pro-apoptotic function of MAP4 could be reversed through the genetic inhibition of MAP4 phosphorylation. The MAP4(Ala) mutant, which mimicked the dephosphorylated form, suppressed mitochondrial translocation and apoptosis. Our data reveal a novel role of MAP4 in cardiac apoptosis and suggest a potential therapeutic strategy targeting mitochondrial translocation of MAP4 against apoptotic heart diseases.

No abstract

Post-stroke depression (PSD) is the most prevalent psychiatric complication of acute ischemic stroke. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) are indicators of inflammation and are associated with stroke and depression. Therefore, the purpose of the present study was to examine the relationship between NLR/PLR and PSD. Retrospective analysis was carried out in 376 patients with first-ever acute ischemic stroke in the First Affiliated Yijishan Hospital of Wannan Medical College between March 2015 and September 2017. Patients were divided into PSD (n=104; 27.7%) and non-PSD (n=272; 72.3%) groups according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria at 6 months after stroke. Clinical data were collected retrospectively. NLR and PLR were acquired retrospectively from the routine blood tests performed at admission. A total of 120 healthy volunteers from the physical examination center in the First Affiliated Yijishan Hospital of Wannan Medical College were recruited as controls. Using logistic regression analysis, NLR (≥4.02) and PLR (≥203.74) were independently associated with PSD. NLR, odds ratio (OR) 3.926, 95% confidence intervals (CI, 2.365-7.947), P<0.001; PLR, OR 3.853, 95% CI (2.214-6.632), P=0.002. The ability of the combined index [area under the receiver operating characteristic curve, 0.701; 95% CI (0.622-0.780); P<0.001] to diagnose PSD was greater than that of either ratio alone. Higher NLRs and PLRs (≥4th quartile) were associated with PSD with a 5.79-fold (P<0.001) increase compared with lower levels of both. Higher NLRs and PLRs were found to be associated with depression 6 months after stroke, and the combined index was more meaningful than either alone in the early clinical detection of PSD.