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Background: Intracerebral hemorrhage (ICH) is a type of stroke which results in a high disability and mortality rate and has a poor prognosis. Tongqiao Huoxue Decoction (TQHXD) is a classical Chinese prescription. Clinical practice has proven that TQHXD can promote blood circulation and can effectively treat ICH and its sequelae. However, the current mechanism is still unclear., Methods: The chemical components and target genes of TQHXD were collected from the Traditional Chinese medicine (TCM) Systems Pharmacology and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine analysis platforms, and the gene expression data of ICH tissues were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to obtain differentially co-expressed gene pairs and build a drug-target-disease network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the obtained target genes and shared genes. Finally, molecular docking was carried out to further clarify the utility of TQHXD for the treatment of ICH., Results: A total of 304 differentially expressed genes in ICH, 42 TQHXD active ingredients, and 279 predicted targets of its active compounds were obtained. Bioinformatics analysis showed that they were involved in angiogenesis, the regulation of wound healing, and other biological processes. Furthermore, their participation in fluid shear stress and the atherosclerosis signaling pathway indicated their close association with the pathological processes of ICH. Finally, molecular docking was carried out to further confirm the tightly binding structural sites of the effective components of TQHXD and key proteins., Conclusions: In summary, the results of this study suggest that the mechanism of action of TQHXD in the treatment of ICH involves multiple targets and signaling pathways related to its occurrence and development. This study not only provides a new theoretical basis for the treatment of ICH with traditional Chinese medicine, but also provides new ideas for the research and development of drugs for the treatment of ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1403/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: This study aimed to systematically compare the discrimination and calibration of 5 clinical scores for stroke-associated pneumonia (SAP) after intracerebral hemorrhage (ICH)., Methods: We derived a validation cohort from the Beijing Registration of Intracerebral Hemorrhage. SAP was then diagnosed according to the Center for Disease Control and Prevention's criteria for hospital-acquired pneumonia. The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration., Results: A total of 1964 patients were enrolled in the study. The mean age was 56.8±14.4 years, and 67.6% were male. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 11 [interquartile range (IQR), 3-21], while the median length of stay (LOS) was 16 days (IQR, 8-22 days). A total of 575 (29.2%) patients were diagnosed with in-hospital SAP after ICH. The AUROC of the 5 clinical scores ranged from 0.732 to 0.800. In comparing these scores, we found that the ICH-associated pneumonia score-B (ICH-APS-B 0.800; 95% CI: 0.780-0.820; P<0.001) showed a statistically better discrimination than did the other risk models (all P<0.001). Furthermore, all clinical scores performed better in patients with an LOS >72 h. The ICH-APS-B (0.827; 95% CI: 0.806-0.848; P<0.001) still showed statistically better discrimination than did the other risk models in patients with an LOS longer than 72 hours. The Hosmer-Lemeshow test also revealed that the ICH-APS-B. had the largest Cox and Snell R2 result for in-hospital SAP after ICH., Conclusions: Among the 5 models for predicting SAP after ICH, the ICH-APS-B showed the best predictive performance, suggests it may be a useful tool for implementing the personalized care of patients and conducting clinical trials of SAP after ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4046/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: The cerebrospinal fluid circulation of patients with intracerebral hemorrhage (ICH) can be blocked by blood clots, resulting in acute hydrocephalus. However, current research on chronic hydrocephalus (CH) is lacking., Methods: A total of 253 patients with ICH combined with coma treated at The Third People's Hospital of Gansu Province after emergency hematoma removal from January 2018 to January 2020 were included. Patients were divided into the CH group (n=48) and the control group (n=205) depending on whether hydrocephalus occurred or not within 3-12 months after operation. The main clinical characteristics of the two groups were compared, and the risk factors for CH were analyzed. Counting data of the two groups were expressed as "n (%)", and multivariate logistic regression analysis was used to explore the risk factors for CH., Results: Compared with the control group, the proportion of patients with modified Graeb score ≥5 points in the CH group increased significantly (52.08% vs. 21.95%, P=0.000). The proportion of patients with preoperative cerebral hernia increased significantly (37.5% vs. 19.51%, P=0.008). The proportion of patients with preoperative obstructive hydrocephalus increased (43.75% vs. 24.39%, P=0.007). The proportion of patients with postoperative subdural effusion increased (41.67% vs. 13.66%, P=0.000). Multivariate logistic regression analysis showed that a modified Graeb score ≥5 points and postoperative subdural effusion were risk factors for the formation of CH in patients with ICH complicated by coma after emergency hematoma removal (P<0.05). The modified Graeb score has diagnostic value for the formation of CH in patients with ICH combined with coma after emergency hematoma removal, and the area under the curve was 0.653 [P=0.001, 95% confidence interval (CI): 0.561-0.744]. There was no significant difference in preoperative neurological deficit score between the control group and the CH group (19.75±3.03 vs. 19.86±3.01, P=0.113). Compared with the control group, the neurological deficit score at 12 months after operation in the CH group was significantly higher (12.73±2.99 vs. 10.64±2.82, P=0.000)., Conclusions: A modified Graeb score >5 points and postoperative subdural effusion are risk factors for the formation of CH in patients with ICH combined with coma after emergency hematoma removal. The formation of CH affects postoperative neurological rehabilitation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-128/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with high morbidity and mortality rates. Oxidative stress and inflammation are important pathological mechanisms of secondary brain injury (SBI) after ICH. Brain and muscle Arnt-like protein 1 (BMAL1), which forms the core component of the circadian clock, was previously shown to be involved in many diseases and to participate in oxidative stress and inflammatory responses. However, the role of BMAL1 in SBI following ICH is unknown. In addition, treatments targeting miR-155 and its downstream signaling pathway may exert a beneficial effect on SBI after ICH, while miR-155 may regulate Bmal1 mRNA stability and translation. Nevertheless, researchers have not clearly determined whetheantagomir-155 upregulates BMAL1 expression and subsequently attenuates ICH-induced brain injury in rats., Methods: After establishing an ICH rat model by injecting autologous blood, the time course of changes in levels of the BMAL1 protein after ICH was analyzed. Subsequently, this study was designed to investigate the potential role and mechanisms of BMAL1 in SBI following ICH using lentiviral overexpression and antagomir-155 treatments., Results: BMAL1 protein levels were significantly decreased in the ICH group compared to the sham group. Genetic overexpression of BMAL1 alleviated oxidative stress, inflammation, brain edema, blood-brain barrier injury, neuronal death, and neurological dysfunction induced by ICH. On the other hand, we observed that inhibiting miRNA-155 using antagomir-155 promoted the expression of BMAL1 and further activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway to attenuate brain injury after ICH., Conclusions: These results reveal that BMAL1 serves as a neuroprotective agent in ICH and upregulation of BMAL1 attenuates ICH-induced SBI. Therefore, BMAL1 may be a promising therapeutic target for SBI following ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1863). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown. This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms., Methods: ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×10 5 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and pro-inflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM)., Results: The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH., Conclusions: Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2590). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration., Methods: The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro . The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH., Results: Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1., Conclusions: Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5839). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: To explore the mechanisms of raw rhubarb and wine-processed rhubarb treatment in a rat model of intracerebral hemorrhage (ICH)., Methods: After adapting to their environment, 30 male Wistar rats were divided into 5 treatment groups: blank control group (CK) (normal saline), sham operation group (SICH) (normal saline), ICH model group (ICH) (normal saline), ICH + raw rhubarb enema group (RO) (raw rhubarb 3.60 g/kg), and ICH + wine-processed rhubarb enema group (WRO) (wine-processed rhubarb 3.60 g/kg). The rhubarb enema (once a day) was given since 3 days before ICH treatment, and was consistently given until 12 hours, 24 hours, 3 days, and 7 days post operation. Serum oxidative stress and inflammatory markers were detected by ELISA, and differences between raw rhubarb and wine-processed rhubarb treatment in ICH rats were screened by proteomics and metabolomics., Results: Both rhubarb treatments effectively improved oxidative stress and inflammatory responses. After ICH, the proteins and metabolites in the brain tissue were significantly altered. Compared with raw rhubarb, wine-processed rhubarb had a better protective effect by dysregulating amino acid metabolism in the ICH model., Conclusions: Our study provides a basis for further research into the mechanisms of rhubarb treatment from different processing technologies, and promotes the application of rhubarb as a therapeutic approach to ICH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7831). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: For patients hospitalized after acute ischemic stroke (AIS), the preadmission comorbidities, level of consciousness (LOC), age and neurologic deficit (PLAN) score can help to identify those who may have a poor outcome. Implementing the PLAN score in other types of stroke may also have predictive value. Our study aimed to evaluate the PLAN score's prognostic accuracy in predicting 1-year mortality and severe disability after intracerebral hemorrhage (ICH)., Methods: We analyzed data found in the China National Stroke Registry (CNSR) of 2,453 hospitalized patients in 132 urban Chinese hospitals, diagnosed with ICH from September 2007 to August 2008. The outcomes analysis included 30-day mortality, modified Rankin Scale score (mRS) of 5-6 at discharge, and 1-year mortality. Univariate and multivariate analysis was performed, and we calculated consistency statistics (C statistic). We evaluated the PLAN score performance using area under the curve (AUC) calculations., Results: We found that the 30-day mortality was 12.6%, the frequency of a mRS 5-6 at discharge was 20.6%, and 1-year mortality was 21.9%. The PLAN score had good predictive value in 30-day mortality (C statistic, 0.82), death or severe dependence at discharge (0.84), and 1-year mortality (0.82)., Conclusions: In patients hospitalized for ICH, the 30-day mortality, death or severe dependence at discharge and 1-year mortality can be predicted by the PLAN score. Similarly to patients hospitalized after AIS, the PLAN score can help to identify patients likely to have poor outcomes following hospitalization for ICH., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)