Despite recent advances in our understanding of the importance of protein surface properties for protein thermostability,there are seldom studies on multi-factors rational design strategy, so a more scientific, simple and effective rational strategy is urgent for protein engineering. Here, we first attempted to use a three-factors rational design strategy combining three common structural features, protein flexibility, protein surface, and salt bridges. Escherichia coli AppA phytase was used as a model enzyme to improve its thermostability. Moreover, the structure and enzyme features of the thermostable mutants designed by our strategy were analyzed roundly. For the single mutants, two (Q206E and Y311K), in five exhibited thermostable property with a higher success rate of prediction (40 %). For the multiple mutants, the themostable sites were combined with another site, I427L, we obtained by directed evolution, Q206E/I427L, Y311K/I427L, and Q206E/Y311K/I427L, all exhibited thermostable property. The Y311K/I427L doubled thermostability (61.7 %, and was compared to 30.97 % after being heated at 80 °C for 10 min) and catalytic efficiency (4.46 was compared to 2.37) improved more than the wild-type AppA phytase almost without hampering catalytic activity. These multi-factors of rational design strategy can be applied practically as a thermostabilization strategy instead of the conventional single-factor approach.
Hemorrhagic stroke is one of the most devastating diseases worldwide due to a high rate of disability and mortality with few effective treatments. Recent advances in nanomedicines to promote hemostasis, drug delivery, neuroprotection, and nerve regeneration may provide insight into hemorrhagic stroke treatment. In this review, we first view the pathophysiology and conventional therapeutics of hemorrhagic stroke. Second, we comprehensively summarize the current nanomedicines applied in hemorrhagic stroke, including inorganic nanomaterials, polymer-based nanomaterials, lipid-based nanomaterials, self-assembling peptide-based hydrogel, exosomes, and gel systems. Finally, the challenges, opportunities, and future perspectives of nanomedicines for hemorrhagic stroke are discussed. Thus, this review promotes greater exploration of effective therapies for hemorrhagic stroke with nanomedicines.
The method of iron-dependent cell death known as ferroptosis is distinct from apoptosis. The suppression of ferroptosis after intracerebral hemorrhage (ICH) will effectively treat ICH and improve prognosis. This paper primarily summarizes the mechanism of ferroptosis after ICH, with an emphasis on lipid peroxidation, the antioxidant system, iron metabolism, and other pathways. In addition, regulatory targets and drug molecules were described. Although there has been some progress in the field of study, there are still numerous gaps. The mechanism by which non-heme iron enters neurons through the blood–brain barrier (BBB), the mitochondrial role in ferroptosis, and the specific mechanism by which lipid peroxidation induces ferroptosis remain unclear and require further study. In addition, the inhibitory effect of many drugs on ferroptosis after ICH has only been demonstrated in basic experiments and must be translated into clinical trials. In summary, research on ferroptosis following ICH will play an important role in the treatment of ICH.
Introduction: Admission hyperglycemia is a common finding after spontaneous intracerebral hemorrhage (ICH) secondary to pre-existing diabetes mellitus (DM) or stress-induced hyperglycemia (SIH). Studies of the causal relationship between SIH and ICH outcomes are rare. Aim: We aimed to identify whether SIH or pre-existing DM was the cause of admission hyperglycemia associated with ICH outcomes. Methods: Admission glycosylated hemoglobin (HbA1c), glucose levels, and comorbidity data from the prospective, multicenter cohort, Chinese Cerebral Hemorrhage: Mechanisms and Intervention Study (CHEERY), were collected and analyzed. According to different admission blood glucose and HbA1c levels, patients were divided into nondiabetic normoglycemia (NDN), diabetic normoglycemia (DN), diabetic hyperglycemia (DH), and SIH groups. Modified Poisson regression models were used to analyze ICH outcomes in the different groups.Results: In total, 1372 patients were included: 388 patients with admission hyperglycemia, 239 with DH, and 149 with SIH. In patients with hyperglycemia, SIH was associated with a higher risk of pulmonary infection [risk ratios (RR): 1.477, 95% confidence interval (CI): 1.004-2.172], 30-day (RR: 1.068, 95% CI: 1.009-1.130) and 90day mortality after ICH (RR: 1.060, 95% CI: 1.000-1.124).Conclusions: Admission hyperglycemia is a common finding after ICH, and SIH is a sensitive predictor of the risk of pulmonary infection and all-cause death after ICH.
Background Intracerebral hemorrhage is the most disabling and lethal form of stroke. We aimed to develop a novel clinical score for neurological deterioration during hospitalization after intracerebral hemorrhage. Methods and Results We analyzed data from the CHERRY (Chinese Cerebral Hemorrhage: Mechanism and Intervention) study. Two‐thirds of eligible patients were randomly allocated into the training cohort (n=1027) and one‐third into the validation cohort (n=515). Multivariable logistic regression was used to identify factors associated with neurological deterioration (an increase in National Institutes of Health Stroke Scale of ≥4 or death) within 15 days after symptom onset. A prediction score was developed based on regression coefficients derived from the logistic model. The site, size, gender, National Institutes of Health Stroke Scale, age, leukocyte, sugar (SIGNALS) score was developed as a sum of individual points (0–8) based on site (1 point for infratentorial location), size (3 points for >20 mL of supratentorial hematoma volume or 2 points for >10 mL of infratentorial hematoma volume), sex (1 point for male sex), National Institutes of Health Stroke Scale score (1 point for >10), age (1 point for ≥70 years), white blood cell (1 point for>9.0×10 9 /L), and fasting blood glucose (1 point>7.0 mmol/L). The proportion of patients who suffered from neurological deterioration increased with higher SIGNALS score, showing good discrimination and good calibration in the training cohort (C statistic, 0.821; Hosmer‐Lemeshow test, P =0.687) and in the validation cohort (C statistic, 0.848; Hosmer‐Lemeshow test, P =0.592), respectively. Conclusions The SIGNALS score reliably predicts the risk of in‐hospital neurological deterioration of patients with intracerebral hemorrhage.
IntroductionHypertension is the most prevalent risk factor for intracerebral hemorrhage (ICH). In this study, we investigated whether preonset anti-hypertensive therapy could affect the outcomes of ICH.MethodsThis was a retrospective cohort study. A total of 3,460 consecutive patients with acute first-ever ICH from 31 recruitment sites were enrolled into the Chinese cerebral hemorrhage: mechanism and intervention (CHERRY) study from December 1, 2018 to November 30, 2020, and 2,140 (61.8%) with hypertension history were entered into the analysis.ResultsOnly 586 patients (27.4%) with hypertension history currently received anti-hypertensive therapy, and which was associated with lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) on admission (SBP, p = 0.008; DBP, p = 0.017), less hematoma volume (9.8 vs. 11%, p = 0.006), and lower all-cause mortality at 3 months (15.3 vs. 19.8%, OR = 0.728, p = 0.016). In multivariable analysis, adjusting for age, gender, residence, ischemic stroke history, admission SBP and DBP, and current use of antihypertension were significantly associated with lower adjusted hazard ratios (HRs) for all-cause mortality at discharge (adjusted HR, 0.497, p = 0.012), 30 days (adjusted HR, 0.712, p = 0.015), and 90 days (adjusted HR, 0.766, p = 0.030). However, after adjusting the variable of hematoma volume, the mortality between the two groups was not significantly different.ConclusionsPreonset anti-hypertensive therapy was associated with lower mortality of ICH, which somewhat depended on hematoma volume.
This study aimed to compare clinical and prognostic characteristics between recurrent and first-ever ICH. Four thousand twelve patients entered the study, and 64% of them were male. The median age is 62 years (interquartile range, 55–71). Among them, 3,750 (93.5%) patients had no experience of previous ICH, and 262 (6.5%) patients were considered as recurrent ICH. We compared demographic data, baseline clinical characteristics, imaging information, hematological parameters, and clinical outcomes between recurrent and first-ever ICH. We found that recurrent ICH was significantly associated with older age, more frequent history of ischemic heart disease, ischemic stroke, hypertension, and hyperlipidemia, while patients with recurrent ICH had previously received more antihypertensive therapy, and showed lower admission blood pressure (median, 160 vs. 167 mmHg) and higher baseline of National Institute of Health stroke scale (NIHSS) score (median, 10 vs. 9). We also demonstrated that recurrent ICH was an independent risk factor of 3-month function dependence after adjusting for many potentially competitive risk factors.
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