Exosomal microRNAs: implications in the pathogenesis and clinical applications of subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe acute neurological disorder with a high fatality rate. Early brain injury (EBI) and cerebral vasospasm are two critical complications of SAH that significantly contribute to poor prognosis. Currently, surgical intervention and interventional therapy are the main treatment options for SAH, but their effectiveness is limited. Exosomes, which are a type of extracellular vesicles, play a crucial role in intercellular communication and have been extensively studied in the past decade due to their potential influence on disease progression, diagnosis, and treatment. As one of the most important components of exosomes, miRNA plays both direct and indirect roles in affecting disease progression. Previous research has found that exosomal miRNA is involved in the development of various diseases, such as tumors, chronic hepatitis, atherosclerosis, diabetes, and SAH. This review focuses on exploring the impact of exosomal miRNA on SAH, including its influence on neuronal apoptosis, inflammatory response, and immune activation following SAH. Furthermore, this review highlights the potential clinical applications of exosomal miRNA in the treatment of SAH. Although current research on this topic is limited and the clinical application of exosomal miRNA has inherent limitations, we aim to provide a concise summary of existing research progress and offer new insights for future research directions and trends in this field.

The occurrence and development of radiation-induced lung injury after interstitial brachytherapy and stereotactic radiotherapy in SD rats.

BACKGROUND: To compare the severity of radiation-induced lung injury (RILI) after the right lung of SD rats received interstitial brachytherapy and stereotactic radiotherapy (SBRT). METHODS: RILI rat model was established using interstitial brachytherapy and SBRT methods, respectively. CT scan was performed to analyze the lung volume and the CT value difference between the left and right lungs in rats. Then the lung tissues were analyzed through H&E staining, peripheral blood was extracted to detect the expression levels of serum inflammatory cytokines, pro-fibrotic cytokines, and fibrotic-inhibiting cytokines by ELISA. RESULTS: The difference between right and left lung CT values was significantly elevated in the SBRT group when compared with the control group and the interstitial brachytherapy group (P < 0.05). The IFN-γ expression in the interstitial brachytherapy group was significantly different from that in the SBRT group at week 1, 4, 8 and 16. Besides, the expressions of IL-2, IL-6 and IL-10 in SBRT group were significantly higher than that of interstitial brachytherapy group (P < 0.05). The TGF-ß expression in interstitial brachytherapy group reached its peak with the increase of time from week 1 to week 16, and it was significantly lower than SBRT group (P < 0.05). The mortality rate in the SBRT group was 16.7%, which was significantly higher than that in the interstitial brachytherapy group. CONCLUSION: The treatment method of interstitial brachytherapy is considered as an effective and safe tool by reducing the side effects of radiotherapy and increasing the radiation dose of radiotherapy.

Neuroprotective and Angiogenesis Effects of Levetiracetam Following Ischemic Stroke in Rats.

Objective: The present study explored whether levetiracetam (LEV) could protect against experimental brain ischemia and enhance angiogenesis in rats, and investigated the potential mechanisms in vivo and in vitro. Methods: The middle cerebral artery was occluded for 60 min to induce middle cerebral artery occlusion (MCAO). The Morris water maze was used to measure cognitive ability. The rotation test was used to assess locomotor function. T2-weighted MRI was used to assess infarct volume. The neuronal cells in the cortex area were stained with cresyl purple. The anti-inflammatory effects of LEV on microglia were observed by immunohistochemistry. Enzyme-linked immunosorbent assays (ELISA) were used to measure the production of pro-inflammatory cytokines. Western blotting was used to detect the levels of heat shock protein 70 (HSP70), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) in extracts from the ischemic cortex. Flow cytometry was used to observe the effect of LEV on neuronal cell apoptosis. Results: LEV treatment significantly increased the density of the surviving neurons in the cerebral cortex and reduced the infarct size (17.8 ± 3.3% vs. 12.9 ± 1.4%, p < 0.01) after MCAO. Concurrently, the time required to reach the platform for LEV-treated rats was shorter than that in the saline group on day 11 after MCAO (p < 0.01). LEV treatment prolonged the rotarod retention time on day 14 after MCAO (84.5 ± 6.7 s vs. 59.1 ± 6.2 s on day 14 compared with the saline-treated groups, p < 0.01). It also suppressed the activation of microglia and inhibited TNF-α and Il-1ß in the ischemic brain (135.6 ± 5.2 pg/ml vs. 255.3 ± 12.5 pg/ml, 18.5 ± 1.3 pg/ml vs. 38.9 ± 2.3 pg/ml on day 14 compared with the saline-treated groups, p < 0.01). LEV treatment resulted in a significant increase in HIF-1α, VEGF, and HSP70 levels in extracts from the ischemic cerebral cortex. At the same time, LEV reduced neuronal cell cytotoxicity and apoptosis induced by an ischemic stroke (p < 0.01). Conclusion: LEV treatment promoted angiogenesis and functional recovery after cerebral ischemia in rats. These effects seem to be mediated through anti-inflammatory and antiapoptotic activities, as well as inducing the expression of HSP70, VEGF, and HIF-1α.

Research update on the anticancer effects of buparlisib.

Buparlisib is a highly efficient and selective PI3K inhibitor and a member of the 2,6-dimorpholinopyrimidine-derived family of compounds. It selectively inhibits four isomers of PI3K, PI3Kα, PI3Kß, PI3Kγ and PI3Kδ, by competitively binding the lipid kinase domain on adenosine 5'-triphosphate (ATP), and serves an important role in inhibiting proliferation, promoting apoptosis and blocking angiogenesis, predominantly by antagonizing the PI3K/AKT pathway. Buparlisib has been confirmed to have a clinical effect in patients with solid tumors and hematological malignancies. A global, phase II clinical trial with buparlisib and paclitaxel in head and neck squamous cell carcinoma has now been completed, with a manageable safety profile. Buparlisib currently has fast-track status with the United States Food and Drug Administration. The present review examined the biochemical structure, pharmacokinetic characteristics, preclinical data and ongoing clinical studies of buparlisib. The various mechanisms of influence of buparlisib in tumors, particularly in preclinical research, were summarized, providing a theoretical basis and direction for basic research on and clinical treatment with buparlisib.

Evaluation of Glymphatic System Using Diffusion MR Technique in T2DM Cases.

Objective: We aimed to evaluate the activity of the human glymphatic system in type 2 diabetes mellitus (T2DM) using diffusion tensor image analysis along with the perivascular space (DTI-ALPS). Methods: Diffusion tensor images were acquired to calculate the diffusivities in the direction of the x-axis (right-to-left; Dx), y-axis (anterior-to-posterior; Dy), and z-axis (inferior-to-superior; Dz) of the plane of the lateral ventricle body in 20 patients with type 2 diabetes and 10 people in a control group. We evaluated the diffusivity along with the perivascular spaces, as well as the projection fibers and association fibers, separately. The analysis along the perivascular space (ALPS-index) was defined as the mean (Dxpro, Dypro)/mean (Dypro, Dzasc), where the Dxpro and Dxasc were the Dx values in the projection and association fiber areas, respectively. Results: There were significant differences in diffusivity along the projection fibers and the association fibers among the groups. The significant differences among the groups along the perivascular spaces, shown as the ALPS-index and medical history of T2DM, indicating lower water diffusivity along the perivascular space concerning type 2 diabetes severity, was also observed. Conclusion: Lower diffusivity along the perivascular space on DTI-APLS can reflect impairment of the glymphatic system in T2DM. This study showed that the activity of the glymphatic system could be evaluated by diffusion tensor image analysis.

Targeting CCL20 inhibits subarachnoid hemorrhage-related neuroinflammation in mice.

Recent evidence suggests that CC chemokine ligand 20 (CCL20) is upregulated after subarachnoid hemorrhage (SAH). Here, we investigated the functions of CCL20 in SAH injury and its underlying mechanisms of action. We found that CCL20 is upregulated in an SAH mouse model and in cultured primary microglia and neurons. CCL20-neutralizing antibody alleviated SAH-induced neurological deficits, decreased brain water content and neuronal apoptosis, and repressed microglial activation. We observed increased levels of CCL20, CC chemokine receptor 6 (CCR6), interleukin 1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α), as well as of microglial activation in microglia treated with oxyhemoglobin (OxyHb). CCL20 or CCR6 knockdown reversed the effects of OxyHb on microglia. Conditioned medium from OxyHb-treated microglia induced neuronal apoptosis, while the percentage of apoptotic neurons in the conditioned medium from microglia transfected with CCL20 siRNA or CCR6 siRNA was decreased. We observed no decrease in OxyHb-induced apoptosis in CCL20-knockdown neurons. Conditioned medium from OxyHb-treated neurons led to microglial activation and induced CCR6, IL-1ß and TNF-α expression, while CCL20 knockdown in neurons or CCR6 knockdown in microglia reversed those effects. Our results thus suggest CCL20 may be targeted to elicit therapeutic benefits after SAH injury.

Corrigendum: Evaluation of Glymphatic System Using Diffusion MR Technique in T2DM Cases.

[This corrects the article DOI: 10.3389/fnhum.2020.00300.].

Treatment Efficacy of the Transsylvian Approach Versus the Transtemporal Cortex Approach to Evacuate Basal Ganglia Hematoma Under a Microscope.

This study aimed to evaluate the clinical efficacy of the transsylvian approach versus the transtemporal cortex approach to evacuate basal ganglia hemorrhage under a microscope. The relevant literature was collected from PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature database, and China National Knowledge Infrastructure databases. The meta-analysis was conducted by Stata 12.0 software. Seven studies were included in the meta-analysis. There were 659 patients, including 329 patients who were treated by the transsylvian approach and 330 patients who were treated by the transtemporal cortex approach. There were significant advantages in the transsylvian approach group, including a high clearance rate of hematoma (OR = 2.361; 95% CI: 1.443-3.861) and a better postoperative recovery (OR = 2.248; 95% CI: 1.598-3.160). A better postoperative recovery could also be found in patients with a history of hypertension (OR = 2.063; 95% CI: 1.429-2.980) and patients whose volume of hematoma ranged from 25 to 60 mL (OR = 2.275; 95% CI: 1.466-3.529). The authors conclude that there are significant advantages to the transsylvian approach, such as a high clearance rate of hematoma and a good postoperative recovery. These advantages should be taken into account when devising appropriate therapeutic strategies for patients with basal ganglia hematoma.

[The safety and efficacy of endoscopic versus microscopic surgery for transsphenoidal pituitary adenoma in China: an updated and cumulative meta-analysis].

OBJECTIVE: To evaluate the present clinical effectiveness and its change trend by an updated and cumulative meta-analysis of endoscopic versus microscopic surgery for transsphenoidal pituitary adenoma in China. METHODS: We conducted a systematic review of the literature related to theme,and the meta-analysis of the data extracted onto a standard form was conducted by State 12.0 software. RESULTS: Finally 14 studies were included. There were 1 888 patients in total including 962 patients receiving endoscopic surgery and 926 patients undergoing microscopic surgery. Compared with microscopic group,there were significant advantages in endoscopic group including the high rate of complete tumor resection (OR=1.951, 95% CI: 1.525-2.495) and the lower incidence of overall operation complication (OR=0.480, 95% CI: 0.298-0.773) and cerebrospinal fluid leakage (OR=0.592, 95% CI: 0.399-0.878), but the advantage of the incidence rate of diabetes insipidus (OR=0.72, 95% CI: 0.420-1.252) was no statistically significant. Cumulative meta-analysis suggested that the advantage of total resection of tumor has stabilized in 2013. CONCLUSION: At present in our country, compared with microscopic group, there were significant advantages in endoscopic group including the rate of complete tumor resection and the incidence of overall operation complications and cerebrospinal fluid leakage, but the advantage of the incidence rate of diabetes insipidus was no statistically significant difference. The follow-up studies related to the rate of total resection of tumor may not change the existing meta-analysis results.

Surgical treatment of Chiari I malformation complicated with syringomyelia.

The aim of this study was to evaluate the curative effects of various surgical procedures on Chiari I malformation (CMI) complicated with syringomyelia. A total of 185 patients with CMI complicated with syringomyelia who received treatment between January 1997 and December 2011 were recruited. All patients underwent posterior fossa decompression in which the lamina of the first cervical vertebra was removed, with the removal of the second or third depending on the severity of the cerebellar tonsil herniation. Of the patients, 76 underwent large-bone-window decompression and duraplasty, while 109 underwent small-bone-window decompression, displaced cerebellar tonsil resection and duraplasty. The curative effects of the different surgical procedures were analyzed retrospectively. Clinical symptoms were eliminated or improved in 156 patients (84.3%) by the time of discharge from hospital. A total of 148 patients were evaluated using magnetic resonance imaging (MRI) which revealed that the cisterna magna was reconstructed in 92 patients and spinal syrinx was reduced in 75. Follow-up was performed on 147 patients (79.5%) for between 3 months and 12 years. During the follow-up, symptoms were eliminated or improved in 110 patients (74.8%), not improved in 26 (17.7%) and deteriorated in 11 (7.5%). MRI was performed on 95 patients during follow-up examinations and the cisterna magna was reconstructed in 87 patients and spinal syrinx was reduced in 79. Small-bone-window decompression plus duraplasty is an effective surgical procedure for treating CMI complicated with syringomyelia and intraoperative cerebellar tonsillectomy significantly aids patient recovery.

Cytokine and chemokine modification by Toll-like receptor polymorphisms is associated with nasopharyngeal carcinoma.

Toll-like receptors (TLR) play a pivotal role in sensing a wide range of pathogens, including bacteria, fungi and viruses. A dysregulation of TLR signaling may increase the risk of developing chronic inflammatory diseases and cancers. The aim of this study was to investigate the association of TLR2 R753Q, TLR4 D299G, and T399I polymorphisms with nasopharyngeal carcinoma (NPC) and to explore the effects of these polymorphisms on cytokine and chemokine expression in NPC biopsies. The genotypes of the three loci among 236 patients with NPC and 287 healthy controls were determined by PCR-RFLP. Cytokines and chemokines mRNA and protein in NPC biopsies were measured by real-time quantitative PCR and ELISA, respectively. Results showed that the combined CT/TT genotype of T399I was associated with increased NPC risk, with an odds ratio of 1.853 (95% confidence interval: 1.184-2.961). Also, individuals with the T allele of T399I showed a 1.842-fold increase in NPC risk compared to those with the T399I C allele (95% confidence interval: 1.213-3.015). Messenger RNA levels of interleukin (IL)-1α, tumor necrosis factor-α and IL-10 were significantly elevated in patients with T399I combined CT/TT genotype; IL-1α and IL-10 protein concentration significantly increased in NPC patients with T399I combined CT/TT genotype compared to those with the T399I CC genotype. Our data suggest that TLR4 T399I modify cytokines and chemokines patterns and play a role in the development of NPC.

Correlation between APOE -491AA promoter in epsilon4 carriers and clinical deterioration in early stage of traumatic brain injury.

The objective of this work was to investigate the relationship between apolipoprotein E (APOE) promoters (G-219T, C-427T, A-491T) polymorphisms and the clinical deterioration in early stage of traumatic brain injury (TBI) in a cohort of Chinese patients. In this study, we used the cohort of patients which has been reported previously. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were admitted from December 2003 to May 2004, and demographic and clinical data were collected. The clinical deterioration of patient's condition in acute stage (<7 days after TBI) was judged by either of the following criteria: decrease of Glasgow Coma Scale (GCS) score (compared with initial admission GCS), increase in hematoma volume or delayed hematoma both detected by repeated computed tomography (CT) scanning compared to that on admission. Venous blood was collected from patients with TBI on admission to determine the APOE promoter polymorphisms. The APOE genotyping was performed by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). chi(2) test and logistic regression analyses were done by SPSS. In 110 Chinese patients, the distributions of APOE genotypes and alleles matched Hardy-Weinberg Law, and 19 subjects presented with deteriorated clinical condition in acute stage after hospitalization. chi(2) test showed insignificant differences in association of APOE promoter polymorphisms with clinical deterioration (p>0.05). But logistic regression analyses, after adjusting patients' age, injury severity and injury mechanism etc, showed that -491AA (OR=11.681, p=0.009, 95%, CI 1.824-74.790) and APOE epsilon4 were all risk factors, with injury severity and alcohol-drinking as other risk factors. In Chinese population, as a significant but not independent risk factor, only APOE -491AA promoter in epsilon4 carriers is apt to the clinical deterioration and may contribute to the poor outcome after TBI.

Effect of APOE polymorphisms on early responses to traumatic brain injury.

To investigate the relationship between apolipoprotein E (APOE) polymorphisms and the severity of traumatic brain injury (TBI) in acute stage in the cohort of mainland Chinese patients. We prospectively identified admissions to the two neurosurgical departments for head injury. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were enrolled from December 2003 to May 2004, and demographic and clinical data were collected. Venous blood was collected from patients with TBI on admission to determine the APOE genotype polymorphisms. The APOE genotyping was performed by means of PCR-RFLP. The deterioration of patients' condition in acute stage (<7 days after TBI) was judged by either of following criteria: decrease of GCS, increase in hematoma volume or delayed hematoma both detected by repeated CT scanning. Chi2-test and logistic regression analyses were done by SPSS. The distributions of APOE genotypes and alleles matched Hardy-Weinberg law. In 110 Chinese patients, 19 subjects presented with deteriorated clinical condition after hospitalization, and seven of 17 patients with APOE epsilon4 (41.2%) had a deteriorated condition which was significantly different from those without APOE epsilon4 (12 of 93 patients, 12.9%, P=0.01). However, neither the presence of epsilon2 nor of epsilon3 was significantly different from those absent of it (P>0.05). Logistic regression analyses showed that APOE epsilon4 was a risk factor (OR=4.836, P=0.011, 95% CI 1.443-16.208) to predispose to clinical deterioration after adjusting for patient age, sex, smoking or not, alcohol-drinking or not, injury severity, injury mechanisms, treatments, and pattern of TBI. This finding suggests that the patients with APOE epsilon4 predispose to clinical deterioration in acute phase after TBI and APOE polymorphisms play a role in early responses to TBI.