Age and mean platelet volume-based nomogram for predicting the therapeutic efficacy of metoprolol in Chinese pediatric patients with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the most common type of orthostatic intolerance in children. We investigated whether platelet-related factors related to treatment efficacy in children suffering from VVS treated with metoprolol. METHODS: Metoprolol-treated VVS patients were recruited. The median duration of therapy was three months. Patients were followed and divided into two groups, treament-effective group and treatment-ineffective group. Logistic and least absolute shrinkage selection operator regressions were used to examine treatment outcome variables. Receiver-operating characteristic (ROC) curves, precision-recall (PR) curves, calibration plots, and decision curve analyses were used to evaluate the nomogram model. RESULTS: Among the 72 patients who complete the follow-up, treatment-effective group and treatment-ineffective group included 42 (58.3%) and 30 (41.7%) cases, respectively. The patients in the treatment-effective group exhibited higher mean platelet volume (MPV) [(11.0 ± 1.0) fl vs. (9.8 ± 1.0) fl, P < 0.01] and platelet distribution width [12.7% (12.3%, 14.3%) vs. 11.3% (10.2%, 12.2%), P < 0.01] than those in the treatment-ineffective group. The sex ratio was significantly different (P = 0.046). A fit model comprising age [odds ratio (OR) = 0.766, 95% confidence interval (CI) = 0.594-0.987] and MPV (OR = 5.613, 95% CI = 2.297-13.711) might predict therapeutic efficacy. The area under the curve of the ROC and PR curves was computed to be 0.85 and 0.9, respectively. The P value of the Hosmer-Lemeshow test was 0.27. The decision curve analysis confirmed that managing children with VVS based on the predictive model led to a net advantage ranging from 0.01 to 0.58. The nomogram is convenient for clinical applications. CONCLUSION: A novel nomogram based on age and MPV can predict the therapeutic benefits of metoprolol in children with VVS.

Endogenous sulfur dioxide deficiency as a driver of cardiomyocyte senescence through abolishing sulphenylation of STAT3 at cysteine 259.

OBJECTIVE: Cardiomyocyte senescence is an important contributor to cardiovascular diseases and can be induced by stressors including DNA damage, oxidative stress, mitochondrial dysfunction, epigenetic regulation, etc. However, the underlying mechanisms for the development of cardiomyocyte senescence remain largely unknown. Sulfur dioxide (SO2) is produced endogenously by aspartate aminotransferase 2 (AAT2) catalysis and plays an important regulatory role in the development of cardiovascular diseases. The present study aimed to explore the effect of endogenous SO2 on cardiomyocyte senescence and the underlying molecular mechanisms. APPROACH AND RESULTS: We interestingly found a substantial reduction in the expression of AAT2 in the heart of aged mice in comparison to young mice. AAT2-knockdowned cardiomyocytes exhibited reduced SO2 content, elevated expression levels of Tp53, p21Cip/Waf, and p16INk4a, enhanced SA-ß-Gal activity, and elevated level of γ-H2AX foci. Notably, supplementation with a SO2 donor ameliorated the spontaneous senescence phenotype and DNA damage caused by AAT2 deficiency in cardiomyocytes. Mechanistically, AAT2 deficiency suppressed the sulphenylation of signal transducer and activator of transcription 3 (STAT3) facilitated its nuclear translocation and DNA-binding capacity. Conversely, a mutation in the cysteine (Cys) 259 residue of STAT3 blocked SO2-induced STAT3 sulphenylation and subsequently prevented the inhibitory effect of SO2 on STAT3-DNA-binding capacity, DNA damage, and cardiomyocyte senescence. Additionally, cardiomyocyte (cm)-specific AAT2 knockout (AAT2cmKO) mice exhibited a deterioration in cardiac function, cardiomegaly, and cardiac aging, whereas supplementation with SO2 donors mitigated the cardiac aging and remodeling phenotypes in AAT2cmKO mice. CONCLUSION: Downregulation of the endogenous SO2/AAT2 pathway is a crucial pathogenic mechanism underlying cardiomyocyte senescence. Endogenous SO2 modifies STAT3 by sulphenylating Cys259, leading to the inhibition of DNA damage and the protection against cardiomyocyte senescence.

Tetramethylpyrazine protects mitochondrial function by up-regulation of TFAM and inhibition of neuronal apoptosis in a rat model of surgical brain injury.

Objectives: Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage and mutation is widely accepted as one of the pathological processes of neurodegenerative diseases. As an mtDNA binding protein, mitochondrial transcription factor A (TFAM) maintains the integrity of mtDNA through transcription, replication, nucleoid formation, damage perception, and DNA repair. In recent works, the overexpression of TFAM increased the mtDNA copy count, promoted mitochondrial function, and improved the neurological dysfunction of neurodegenerative diseases. The role of TFAM in neurodegenerative diseases has been well explained. However, the role of TFAM after surgical brain injury (SBI) has not been studied. In this work, we aimed to study the role of TFAM in the brain after SBI and its mechanism of action. Materials and Methods: One hour after the occurrence of SBI, tetramethylpyrazine (TMP) was injected into the abdominal cavity of rats, and the brain was collected 48 hr later for testing. The evaluation included neurobehavioral function test, brain water content measurement, immunofluorescence, western blot, TUNEL staining, FJC staining, ROS test, and ATP test. Results: After SBI, the content of TFAM on the ipsilateral side increased and reached a peak at about 48 hr. After intraperitoneal injection of TMP in rats, 48 hr after SBI, the concentration of TFAM, Bcl-2, and adenosine triphosphate (ATP) increased; the content of caspase-3, reactive oxygen species (ROS), and cerebral edema decreased; and the nerve function significantly improved. Conclusion: TMP inhibited cell apoptosis after SBI in rats by up-regulating TFAM and protecting brain tissues.

Gasotransmitter-Mediated Cysteinome Oxidative Posttranslational Modifications: Formation, Biological Effects, and Detection.

Significance: Gasotransmitters, including nitric oxide (NO), hydrogen sulfide (H2S) and sulfur dioxide (SO2), participate in various cellular processes via corresponding oxidative posttranslational modifications (oxiPTMs) of specific cysteines. Recent Advances: Accumulating evidence has clarified the mechanisms underlying the formation of oxiPTMs derived from gasotransmitters and their biological functions in multiple signal pathways. Because of the specific existence and functional importance, determining the sites of oxiPTMs in cysteine is crucial in biology. Recent advances in the development of selective probes, together with upgraded mass spectrometry (MS)-based proteomics, have enabled the quantitative analysis of cysteinome. To date, several cysteine residues have been identified as gasotransmitter targets. Critical Issues: To clearly understand the underlying mechanisms for gasotransmitter-mediated biological processes, it is important to identify modified targets. In this review, we summarize the chemical formation and biological effects of gasotransmitter-dependent oxiPTMs and highlight the state-of-the-art detection methods. Future Directions: Future studies in this field should aim to develop the next generation of probes for in situ labeling to improve spatial resolution and determine the dynamic change of oxiPTMs, which can lay the foundation for research on the molecular mechanisms and clinical translation of gasotransmitters. Antioxid. Redox Signal. 40, 145-167.

Role of Lipocalin-2 in N1/N2 Neutrophil Polarization After Stroke.

BACKGROUND: Neutrophils and Lipocalin-2 (LCN2) play pivotal roles in cerebral ischemiareperfusion (I/R) injury. However, their contribution is not fully clarified. OBJECTIVE: This study aimed to explore the role of LCN2 and its association with neutrophil polarization in I/R injury. METHODS: A mouse model of middle cerebral artery occlusion (MCAO) was used to induce cerebral ischemia. LCN2mAb was administered 1 h and Anti-Ly6G was administered for 3d before MCAO. The role of LCN2 in the polarity transition of neutrophils was explored using an in vitro HL-60 cell model. RESULTS: LCN2mAb pretreatment had neuroprotective effects in mice. The expression of Ly6G was not significantly different, but the expression of N2 neutrophils was increased. In the in vitro study, LCN2mAb-treated N1-HL-60 cells induced N2-HL-60 polarization. CONCLUSION: LCN2 may affect the prognosis of ischemic stroke by mediating neutrophil polarization.

Impoverished language in early childhood affects the development of complex sentence structure.

The hypothesis that impoverished language experience affects complex sentence structure development around the end of early childhood was tested using a fully randomized, sentence-to-picture matching study in American Sign Language (ASL). The participants were ASL signers who had impoverished or typical access to language in early childhood. Deaf signers whose access to language was highly impoverished in early childhood (N = 11) primarily comprehended structures consisting of a single verb and argument (Subject or Object), agreeing verbs, and the spatial relation or path of semantic classifiers. They showed difficulty comprehending more complex sentence structures involving dual lexical arguments or multiple verbs. As predicted, participants with typical language access in early childhood, deaf native signers (N = 17) or hearing second-language learners (N = 10), comprehended the range of 12 ASL sentence structures, independent of the subjective iconicity or frequency of the stimulus lexical items, or length of ASL experience and performance on non-verbal cognitive tasks. The results show that language experience in early childhood is necessary for the development of complex syntax. RESEARCH HIGHLIGHTS: Previous research with deaf signers suggests an inflection point around the end of early childhood for sentence structure development. Deaf signers who experienced impoverished language until the age of 9 or older comprehend several basic sentence structures but few complex structures. Language experience in early childhood is necessary for the development of complex sentence structure.

Poincaré plot can help predict the curative effect of metoprolol for pediatric postural orthostatic tachycardia syndrome.

Purpose: To study whether a Poincaré plot can help predict the curative effect of metoprolol for postural orthostatic tachycardia syndrome (POTS) in children. Methods: Pediatric patients with POTS who were administered metoprolol were retrospectively included. The collected data included general data (sex, age, height, weight, and body mass index), the manifestations and treatment (baseline orthostatic intolerance symptom score and course of metoprolol treatment), vital signs (supine heart rate [HR], supine blood pressure, and increased HR during the standing test), HR variability indexes (standard deviation of normal-to-normal intervals [SDNN]; standard deviation of the averages of normal-to-normal intervals [SDANN]; mean standard deviation of the NN intervals for each 5-min segment [SDNNI]; root mean square of the successive differences [rMSSD]; percentage of adjacent NN intervals that differ by >50 ms [pNN50]; triangular index; ultra-low [ULF], very low [VLF], low [LF], and high frequency [HF]; total power [TP]; and LF/HF ratio), and graphical parameters of the Poincaré plot (longitudinal axis [L], transverse axis [T], and L/T). Receiver operator characteristic curves were used to calculate the predictive function of the indexes with significant differences between patients who responded and those who did not. The index combination with the highest predictive value was obtained through series-parallel analysis. Results: Overall, 40 responders and 23 non-responders were included. The L and T in the Poincaré plots and rMSSD, pNN50, HF, and TP of the HR variability data were significantly lower in participants who responded to metoprolol than in participants who did not (p < 0.001). The L/T of participants who responded to metoprolol was greater than that of non-responders (p < 0.001). Moreover, we noted a strong correlation between every two indexes among L, T, rMSSD, pNN50, HF, TP, and L/T (p < 0.05). T < 573.9 ms combined with L/T > 2.9 had the best performance for predicting the effectiveness of metoprolol, with a sensitivity of 85.0%, specificity of 82.6%, and accuracy of 84.1%. Conclusion: In the Poincaré plot, a T < 573.9 ms combined with an L/T > 2.9 helps predict good outcomes of using metoprolol to treat pediatric POTS.

Potential mechanism of TMEM2/CD44 in endoplasmic reticulum stress­induced neuronal apoptosis in a rat model of traumatic brain injury.

Traumatic brain injury (TBI) can lead to the disruption of endoplasmic reticulum (ER) homeostasis in neurons and induce ER stress. Transmembrane protein 2 (TMEM2) may regulate ER stress through the p38/ERK signaling pathway, independent of the classic unfolded protein response (UPR) pathway. The present study examined the expression of TMEM2 following TBI in a rat model, in an aim to determine whether the mitogen­activated protein kinase (MAPK) signaling pathway is controlled by TMEM2/CD44 to mitigate secondary brain injury. For this purpose, 89 Sprague­Dawley rats were used to establish the model of TBI, and TMEM2 siRNA was used to silence TMEM2. Western blot analysis, immunofluorescence, TUNEL assay and Fluoro­Jade C staining, the wet­dry method and behavioral scoring were used for analyses. The results revealed that TMEM2 was activated following TBI in rats. The silencing of TMEM2 resulted in a significant increase in the levels of p38 and ERK (components of MAPK signaling), while brain edema, neuronal apoptosis and degeneration were significantly aggravated. TBI increased TMEM2/CD44­aggravated brain edema and neurological impairment, possibly by regulating ERK and p38 signaling. TMEM2/CD44 may thus be a target for the prevention and control of TBI.

Effect of CrF3 Addition on Photoluminescence Properties of Lead-Free Cs4SnBr6-xFx Zero-Dimensional Perovskite.

Zero-dimensional (0D) tin halide perovskites, characterized by their broadband and adjustable emissions, high photoluminescence quantum yield, and absence of self-absorption, are crucial for the fabrication of high-efficiency optoelectronic devices, such as LEDs, solar cells, and sensors. Despite these attributes, boosting their emission efficiency and stability poses a significant challenge. In this work, Cr3+-doped Cs4SnBr6-xFx perovskites were synthesized using a water-assisted wet ball-milling method. The effect of CrF3 addition on photoluminescence properties of Cs4SnBr6-xFx Perovskites was investigated. We found that Cr3+-doped Cs4SnBr6-xFx Perovskites exhibit a broad emission band, a substantial Stokes shift, and an efficient green light emission centered at about 525 nm at ambient temperature. The derived photoluminescence quantum yield amounted to as high as 56.3%. In addition, these Cr3+-doped Cs4SnBr6-xFx perovskites outperform their undoped counterparts in terms of thermal stability. Through a comprehensive analysis of photoluminescence measurements, our findings suggested that the elevated photoluminescence quantum yield can be attributed to the enhanced exciton binding energy of self-trapped excitons (STEs) and the suitable electron-phonon coupling resulting from the substantial distortion of [SnBr6]4- octahedra instigated by the addition of CrF3.

L-cystathionine protects against oxidative stress and DNA damage induced by oxidized low-density lipoprotein in THP-1-derived macrophages.

Introduction: Oxidative stress in monocyte-derived macrophages is a significant pathophysiological process in atherosclerosis. L-cystathionine (L-Cth) acts as a scavenger for oxygen free radicals. However, the impact of L-Cth on macrophage oxidative stress during atherogenesis has remained unclear. This study aimed to investigate whether L-Cth affects oxidative stress in THP-1-derived macrophages and its subsequent effects on DNA damage and cell apoptosis. Methods: We established a cellular model of oxLDL-stimulated macrophages. The content of superoxide anion, H2O2, NO, and H2S in the macrophage were in situ detected by the specific fluorescence probe, respectively. The activities of SOD, GSH-Px, and CAT were measured by colorimetrical assay. The protein expressions of SOD1, SOD2, and iNOS were detected using western blotting. The DNA damage and apoptosis in the macrophage was evaluated using an fluorescence kit. Results: The results demonstrated that oxLDL significantly increased the content of superoxide anion and H2O2, the expression of iNOS protein, and NO production in macrophages. Conversely, oxLDL decreased the activity of antioxidants GSH-Px, SOD, and CAT, and downregulated the protein expressions of SOD1 and SOD2 in macrophages. However, treatment with L-Cth reduced the levels of superoxide anion, H2O2, and NO, as well as the protein expression of iNOS induced by oxLDL. Moreover, L-Cth treatment significantly enhanced GSH-Px, SOD, and CAT activity, and upregulated the expressions of SOD1 and SOD2 proteins in macrophages treated with oxLDL. Furthermore, both L-Cth supplementation and activation of endogenous L-Cth production suppressed DNA damage and cell apoptosis in oxLDL-injured macrophages, whereas inhibition of endogenous L-Cth exacerbated the deleterious effects of oxLDL. Conclusion: These findings suggest that L-Cth exerts a pronounced inhibitory effect on the oxidative stress, subsequent DNA damage and cell apoptosis in oxLDL-stimulated THP-1 monocytes. This study deepens our understanding of the pathogenesis of macrophage-related cardiovascular pathology.

Hypoxia inducible factor-1α is an important regulator of macrophage biology.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and ß subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

The prognostic value of deep earlobe creases in patients with acute ischemic stroke.

Background and purpose: Data on earlobe crease (ELC) among patients with acute ischemic stroke (AIS) are limited. Here, we determined the frequency and characteristics of ELC and the prognostic effect of ELC among AIS patients. Methods: A total of 936 patients with acute AIS were enrolled during the period between December 2018 and December 2019. The patients were divided into those without and with ELC, unilateral and bilateral ELC, and shallow and deep ELC, according to the photographs taken of the bilateral ears. Logistic regression models were used to estimate the effect of ELC, bilateral ELC, and deep ELC on poor functional outcomes at 90 days (a modified Rankin Scale score ≥2) in AIS patients. Results: Among the 936 AIS patients, there were 746 (79.7%) patients with ELC. Among patients with ELC, there were 156 (20.9%) patients with unilateral ELC and 590 (79.1%) with bilateral ELC and 476 (63.8%) patients with shallow ELC and 270 (36.2%) with deep ELC. After adjusting for age, sex, baseline NIHSS score, and other potential covariates, patients with deep ELC were associated with a 1.87-fold [odds ratio (OR) 1.87; 95% confidence interval (CI), 1.13-3.09] and 1.63-fold (OR 1.63; 95%CI, 1.14-2.34) increase in the risk of poor functional outcome at 90 days in comparison with those without ELC or shallow ELC. Conclusion: ELC was a common phenomenon, and eight out of ten AIS patients had ELC. Most patients had bilateral ELC, and more than one-third had deep ELC. Deep ELC was independently associated with an increased risk of poor functional outcome at 90 days.

Synthesis and Improved Photoluminescence of SnF2-Derived CsSnCl3-SnF2:Mn2+ Perovskites via Rapid Thermal Treatment.

We report a rapid synthesis method for producing CsSnCl3:Mn2+ perovskites, derived from SnF2, and investigate the effects of rapid thermal treatment on their photoluminescence properties. Our study shows that the initial CsSnCl3:Mn2+ samples exhibit a double luminescence peak structure with PL peaks at approximately 450 nm and 640 nm, respectively. These peaks originate from defect-related luminescent centers and the 4T1→6A1 transition of Mn2+. However, as a result of rapid thermal treatment, the blue emission is significantly reduced and the red emission intensity is increased nearly twofold compared to the pristine sample. Furthermore, the Mn2+-doped samples demonstrate excellent thermal stability after the rapid thermal treatment. We suggest that this improvement in photoluminescence results from enhanced excited-state density, energy transfer between defects and the Mn2+ state, as well as the reduction of nonradiative recombination centers. Our findings provide valuable insights into the luminescence dynamics of Mn2+-doped CsSnCl3 and open up new possibilities for controlling and optimizing the emission of rare-earth-doped CsSnCl3.

Podoplanin: A potential therapeutic target for thrombotic diseases.

As a specific lymphatic marker and a key ligand of C-type lectin-like receptor 2 (CLEC-2), podoplanin (Pdpn) is involved in various physiological and pathological processes such as growth and development, respiration, blood coagulation, lymphangiogenesis, angiogenesis, and inflammation. Thrombotic diseases constitute a major cause of disability and mortality in adults, in which thrombosis and inflammation play a crucial role. Recently, increasing evidence demonstrates the distribution and function of this glycoprotein in thrombotic diseases such as atherosclerosis, ischemic stroke, venous thrombosis, ischemic-reperfusion injury (IRI) of kidney and liver, and myocardial infarction. Evidence showed that after ischemia, Pdpn can be acquired over time by a heterogeneous cell population, which may not express Pdpn in normal conditions. In this review, the research progresses in understanding the roles and mechanisms of podoplanin in thromobotic diseases are summarized. The challenges of podoplanin-targeted approaches for disease prognosis and preventions are also discussed.

Hydrogen Sulfide Regulates Macrophage Function in Cardiovascular Diseases.

Significance: Hydrogen sulfide (H2S) is an endogenous gasotransmitter that plays a vital role in immune system regulation. Recently, the regulation of macrophage function by H2S has been extensively and actively recognized. Recent Advances: The mechanisms by which endogenous H2S controls macrophage function have attracted increasing attention. The generation of endogenous H2S from macrophages is mainly catalyzed by cystathionine-γ-lyase. H2S is involved in the macrophage activation and inflammasome formation, which contributes to macrophage apoptosis, adhesion, chemotaxis, and polarization. In addition, H2S has redox ability and interacts with reactive oxygen species to prevent oxidative stress. Moreover, H2S epigenetically regulates gene expression. Critical Issues: In this article, the generation of endogenous H2S in macrophages and its regulatory effect on macrophage function are reviewed. In addition, the signal transduction targeting macrophages by H2S is also addressed. Finally, the potential therapeutic effect of H2S on macrophages is discussed. Future Directions: Further experiments are required to explore the involvement of endogenous H2S in the regulation of macrophage function in various physiological and pathophysiological processes and elucidate the mechanisms involved. Regarding the clinical translation of H2S, further exploration of the application of H2S in inflammation-related diseases is needed. Antioxid. Redox Signal. 38, 45-56.

Combined prognostic significance of white blood cell count and D-dimer on in-hospital outcomes of acute ischemic stroke.

BACKGROUND AND AIMS: The prognostic significance of combination of white blood cell (WBC) and D-dimer on acute ischemic stroke (AIS) remains to be explored. We aimed to investigate the combined effect of WBC and D-dimer levels on in-hospital outcomes of AIS patients. METHODS AND RESULTS: 801 AIS patients were included. Patients were divided into four groups according to the cut-point identified by receiver operating characteristic (ROC) curve of D-dimer (1.105 µg/L) and WBC (7.05 × 109/L): LWLD (low WBC count and low D-dimer), LWHD (low WBC count and high D-dimer), HWLD (high WBC count and low D-dimer), and HWHD (high WBC count and high D-dimer). HWHD group had the highest cumulative incidence of in-hospital mortality (hazard ratio, 5.79; 95%CI, 1.71-19.58, P = 0.006). Patients in HWHD group were 4.14 fold more likely to have in-hospital pneumonia (odds ratio, 4.14; 95%CI, 2.09-8.21; P < 0.001), compared with those in LWLD group. The area under curve (AUC) of the combination of WBC and D-dimer levels for in-hospital mortality and pneumonia was larger than that of WBC and D-dimer alone (0.920 vs. 0.900 vs. 0.915; 0.831 vs. 0.829 vs. 0.807). CONCLUSIONS: The combination of WBC count and D-dimer levels at admission was independently associated with in-hospital outcomes of AIS patients. The addition of WBC to D-dimer levels had a tendency to improve the predictive power for in-hospital mortality and pneumonia.

Early Cognitive Impairment at Acute Stage After Intracerebral Hemorrhage.

BACKGROUND: Cognitive impairment after acute intracerebral hemorrhage (ICH) is common. While the evidence of early cognitive impairment at the acute stage after ICH is limited. We determined the frequency and risk factors of early cognitive impairment at the acute stage and investigated its association with delayed cognitive impairment after ICH. METHODS: A total of 208 patients with acute ICH were enrolled from January 2017 to February 2019. Cognitive function was assessed during the acute stage and at follow-up using Montreal Cognitive Assessment (MoCA) score. Significant cognitive impairment was defined as having a MoCA score <20 at the acute stage (within 1 week after hospital admission) or during follow-up. RESULTS: The mean observation period was 20 (IQC 17-23) months, and follow-up cognitive function data were collected from 185 patients. 89 (42.8%) and 86 (46.5%) patients had an acute stage and delayed significant cognitive impairment, respectively. Older age, large baseline hematoma volume, more severe ICH, and low level of education were significantly associated with significant cognitive impairment at the acute stage (all P ≤ 0.009). In the multivariable logistic regression model, the low MoCA score (odds ratio [OR] 0.59; 95% confidence interval [CI] 0.48-0.71; P<0.001) at the acute stage was independently associated with delayed significant cognitive impairment after ICH. CONCLUSION: Near half of the patients had significant cognitive impairment at the acute stage after ICH. Cognitive impairment is more frequent in the elderly, those with large baseline hematoma volume, and more severe initial neurological deficit. Having a lower MoCA score during the acute phase was independently associated with an increased risk of delayed cognitive impairment.

Podoplanin: Its roles and functions in neurological diseases and brain cancers.

Podoplanin is a small mucin-like glycoprotein involved in several physiological and pathological processes in the brain including development, angiogenesis, tumors, ischemic stroke and other neurological disorders. Podoplanin expression is upregulated in different cell types including choroid plexus epithelial cells, glial cells, as well as periphery infiltrated immune cells during brain development and neurological disorders. As a transmembrane protein, podoplanin interacts with other molecules in the same or neighboring cells. In the past, a lot of studies reported a pleiotropic role of podoplanin in the modulation of thrombosis, inflammation, lymphangiogenesis, angiogenesis, immune surveillance, epithelial mesenchymal transition, as well as extracellular matrix remodeling in periphery, which have been well summarized and discussed. Recently, mounting evidence demonstrates the distribution and function of this molecule in brain development and neurological disorders. In this review, we summarize the research progresses in understanding the roles and mechanisms of podoplanin in the development and disorders of the nervous system. The challenges of podoplanin-targeted approaches for disease prognosis and preventions are also discussed.

Endogenous Hydrogen Sulfide Persulfidates Caspase-3 at Cysteine 163 to Inhibit Doxorubicin-Induced Cardiomyocyte Apoptosis.

Doxorubicin (DOX) is an efficient antitumor anthracycline drug, but its cardiotoxicity adversely affects the prognosis of the patients. In this study, we explored whether endogenous gasotransmitter hydrogen sulfide (H2S) could protect against DOX-induced cardiomyocyte apoptosis and its mechanisms. The results indicated that DOX significantly downregulated endogenous H2S production and endogenous synthetase cystathionine γ-lyase (CSE) expression and obviously stimulated the apoptosis in H9C2 cells. The supplement of H2S donor sodium hydrosulfide (NaHS) or overexpression of CSE inhibited DOX-induced H9C2 cell apoptosis. DOX enhanced the activities of caspase family members in cardiomyocytes, while NaHS attenuated DOX-enhanced caspase-3, caspase-2, and caspase-9 activities by 223.1%, 73.94%, and 52.29%, respectively. Therefore, taking caspase-3 as a main target, we demonstrated that NaHS or CSE overexpression alleviated the cleavage of caspase-3, suppressed caspase-3 activity, and inhibited the cleavage of poly ADP-ribose polymerase (PARP). Mechanistically, we found that H2S persulfidated caspase-3 in H9C2 cells and human recombinant caspase-3 protein, while the thiol-reducing agent dithiothreitol (DTT) abolished H2S-induced persulfidation of caspase-3 and thereby prevented the antiapoptotic effect of H2S on caspase-3 in H9C2 cells. The mutation of caspase-3 C148S and C170S failed to block caspase-3 persulfidation by H2S in H9C2 cells. However, caspase-3 C163S mutation successfully abolished the effect of H2S on caspase-3 persulfidation and the corresponding protection of H9C2 cells. Collectively, these findings indicate that endogenous H2S persulfidates caspase-3 at cysteine 163, inhibiting its activity and cardiomyocyte apoptosis. Sufficient endogenous H2S might be necessary for the protection against myocardial cell apoptosis induced by DOX. The results of the study might open new avenues with respect to the therapy of DOX-stimulated cardiomyopathy.

OsHYPK-mediated protein N-terminal acetylation coordinates plant development and abiotic stress responses in rice.

N-terminal acetylation is one of the most common protein modifications in eukaryotes, and approximately 40% of human and plant proteomes are acetylated by ribosome-associated N-terminal acetyltransferase A (NatA) in a co-translational manner. However, the in vivo regulatory mechanism of NatA and the global impact of NatA-mediated N-terminal acetylation on protein fate remain unclear. Here, we identify Huntingtin Yeast partner K (HYPK), an evolutionarily conserved chaperone-like protein, as a positive regulator of NatA activity in rice. We found that loss of OsHYPK function leads to developmental defects in rice plant architecture but increased resistance to abiotic stresses, attributable to perturbation of the N-terminal acetylome and accelerated global protein turnover. Furthermore, we demonstrated that OsHYPK is also a substrate of NatA and that N-terminal acetylation of OsHYPK promotes its own degradation, probably through the Ac/N-degron pathway, which could be induced by abiotic stresses. Taken together, our findings suggest that the OsHYPK-NatA complex plays a critical role in coordinating plant development and stress responses by dynamically regulating NatA-mediated N-terminal acetylation and global protein turnover, which are essential for maintaining adaptive phenotypic plasticity in rice.