Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

BACKGROUND: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. METHODS: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. RESULT: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. CONCLUSION: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

Extracellular vesicles: A new communication paradigm of complement in neurological diseases.

The complement system is crucial to the innate immune system. It has the function of destroying pathogens by activating the classical, alternative, and lectin pathways. The complement system is important in nervous system diseases such as cerebrovascular and neurodegenerative diseases. Activation of the complement system involves a series of intercellular signaling and cascade reactions. However, research on the source and transport mechanisms of the complement system in neurological diseases is still in its infancy. Studies have increasingly found that extracellular vesicles (EVs), a classic intercellular communication paradigm, may play a role in complement signaling disorders. Here, we systematically review the EV-mediated activation of complement pathways in different neurological diseases. We also discuss the prospect of EVs as future immunotherapy targets.

Diabetic and stress-induced hyperglycemia in spontaneous intracerebral hemorrhage: A multicenter prospective cohort (CHEERY) study.

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 90-day 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.

ADVISING score: a reliable grading scale based on injury and response for intracerebral haemorrhage.

BACKGROUND: Intracerebral haemorrhage (ICH) is the most devastating form of stroke causing high morbidity and mortality. We aimed to develop a novel clinical score incorporating multisystem markers to predict functional dependence at 90 days after ICH. METHODS: We analysed data from Chinese Cerebral Hemorrhage: Mechanism and Intervention study. Multivariable logistic regression analysis was used to identify the factors associated with 90-day functional dependency (the modified Rankin Scale ≥3) after ICH and develop the ADVISING scoring system. To test the scoring system, a total of 2111 patients from Hubei province were included as the training cohort, and 733 patients from other three provinces in China were included as an external validation cohort. RESULTS: We found nine variables to be significantly associated with functional dependency and included in the ADVISING score system: age, deep location of haematoma, volume of haematoma, National Institutes of Health Stroke Scale, aspartate transaminase, international normalised ratio, neutrophil-lymphocyte ratio, fasting blood glucose and glomerular filtration rate. Individuals were divided into 12 different categories by using these nine potential predictors. The proportion of patients who were functionally dependent increased with higher ADVISING scores, which showed good discrimination and calibration in both the training cohort (C-statistic, 0.866; p value of Hosmer-Lemeshow test, 0.195) and validation cohort (C-statistic, 0.884; p value of Hosmer-Lemeshow test, 0.853). The ADVISING score also showed better discriminative performance compared with the other five existing ICH scores (p<0.001). CONCLUSIONS: ADVISING score is a reliable tool to predict functional dependency at 90 days after ICH.

Prediction of Neurological Deterioration After Intracerebral Hemorrhage: The SIGNALS Score.

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>9.0×109/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.

Nanomedicine: An Emerging Novel Therapeutic Strategy for Hemorrhagic Stroke.

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.

Clinical and Prognostic Characteristics of Recurrent Intracerebral Hemorrhage: A Contrast to First-Ever ICH.

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.

Genetics of Spontaneous Intracerebral Hemorrhage: Risk and Outcome.

Spontaneous intracerebral hemorrhage (ICH) is a common fatal event without an effective therapy. Of note, some familial aggregation and inherited tendency is found in ICH and heritability estimates indicate that genetic variations contribute substantially to ICH risk and outcome. Thus, identification of genetic variants that affect the occurrence and outcome may be helpful for ICH prevention and therapy. There are several reviews summarizing numerous genetic variants associated with the occurrence of ICH before, but genetic variants contributing to location distribution and outcome have rarely been introduced. Here, we summarize the current knowledge of genetic variants and pay special attention to location distribution and outcome. So far, investigations have reveled variations in APOE, GPX1, CR1, ITGAV, PRKCH, and 12q21.1 are associated with lobar ICH (LICH), while ACE, COL4A2, 1q22, TIMP1, TIMP2, MMP2, MMP9, and TNF are associated with deep ICH (DICH). Moreover, variations in APOE, VWF, 17p12, HP, CFH, IL6ST, and COL4A1 are possible genetic contributors to ICH outcome. Furthermore, the prospects for ICH related genetic studies from the bench to the bed were discussed.

Neuron derived fractalkine promotes microglia to absorb hematoma via CD163/HO-1 after intracerebral hemorrhage.

BACKGROUND: Hematoma leads to progressive neurological deficits and poor outcomes after intracerebral hemorrhage (ICH). Early clearance of hematoma is widely recognized as an essential treatment to limit the damage and improve the clinical prognosis. CD163, alias hemoglobin (Hb) scavenger receptor on microglia, plays a pivotal role in hematoma absorption, but CD163 on neurons permits Hb uptake and results in neurotoxicity. In this study, we focus on how to specially promote microglial but not neuronal CD163 mediated-Hb uptake and hematoma absorption. METHODS: RNA sequencing was used to explore the potential molecules involved in ICH progression, and hematoma was detected by magnetic resonance imaging (MRI). Western blot and immunofluorescence were used to evaluate the expression and location of fractalkine (FKN) after ICH. Erythrophagocytosis assay was performed to study the specific mechanism of action of FKN in hematoma clearance. Small interfering RNA (siRNA) transfection was used to explore the effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) on hematoma absorption. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum FKN concentration in ICH patients. RESULTS: FKN was found to be significantly increased around the hematoma in a mouse model after ICH. With its unique receptor CX3CR1 in microglia, FKN significantly decreased the hematoma size and Hb content, and improved neurological deficits in vivo. Further, FKN could enhance erythrophagocytosis of microglia in vitro via the CD163/ hemeoxygenase-1 (HO-1) axis, while AZD8797 (a specific CX3CR1 inhibitor) reversed this effect. Moreover, PPAR-γ was found to mediate the increase in the CD163/HO-1 axis expression and erythrophagocytosis induced by FKN in microglia. Of note, a higher serum FKN level was found to be associated with better hematoma resolution in ICH patients. CONCLUSIONS: We systematically identified that FKN may be a potential therapeutic target to improve hematoma absorption and we shed light on ICH treatment.

Association Between Preonset Anti-hypertensive Treatment and Intracerebral Hemorrhage Mortality: A Cohort Study From CHEERY.

Introduction: Hypertension 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. Methods: This 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. Results: Only 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. Conclusions: Preonset anti-hypertensive therapy was associated with lower mortality of ICH, which somewhat depended on hematoma volume.

Ferroptosis and Iron Metabolism after Intracerebral Hemorrhage.

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.

A multi-factors rational design strategy for enhancing the thermostability of Escherichia coli AppA phytase.

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.