Combining metabolomics and network pharmacology to investigate the protective effect of Jiawei Xinglou Chengqi Granules in ischemic stroke.

Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways.

Aberrant Brain Networks and Relative Band Power in Patients with Acute Anti-NMDA Receptor Encephalitis: A Study of Resting-State EEG.

OBJECTIVE: The alterations of the functional network (FN) in anti-N-methyl-Daspartate receptor (NMDAR) encephalitis have been recognized by functional magnetic resonance imaging studies. However, few studies using the electroencephalogram (EEG) have been performed to explore the possible FN changes in anti-NMDAR encephalitis. In this study, the aim was to explore any FN changes in patients with anti-NMDAR encephalitis. METHODS: Twenty-nine anti-NMDAR encephalitis patients and 29 age- and gender-matched healthy controls (HC) were assessed using 19-channel EEG examination. For each participant, five 10-second epochs of resting state EEG with eyes closed were extracted. The cortical source signals of 84 Brodmann areas were calculated using the exact low resolution brain electromagnetic tomography (eLORETA) inverse solution by LORETA-KEY. Phase Lag Index (PLI) matrices were then obtained and graph and relative band power (RBP) analyses were performed. RESULTS: Compared with healthy controls, functional connectivity (FC) in the delta, theta, beta 1 and beta 2 bands significantly increased within the 84 cortical source signals of anti-NMDAR encephalitis patients (p < 0.05) and scalp FC in the alpha band decreased within the 19 electrodes. Additionally, the anti-NMDAR encephalitis group exhibited higher local efficiency and clustering coefficient compared to the healthy control group in the four bands. The slowing band RBP increased while the fast band RBP decreased in multiple-lobes and some of these changes in RBP were correlated with the modified Rankin Scale (mRS) and Mini-mental State Examination (MMSE) in anti-NMDAR encephalitis patients. CONCLUSIONS: This study further deepens the understanding of related changes in the abnormal brain network and power spectrum of anti-NMDA receptor encephalitis. The decreased scalp alpha FC may indicate brain dysfunction, while the increased source beta FC may indicate a compensatory mechanism for brain function in anti-NMDAR encephalitis patients. These findings extend understanding of how the brain FN changes from a cortical source perspective. Further studies are needed to detect correlations between altered FNs and clinical features and characterize their potential value for the management of anti-NMDAR encephalitis.

Exploring brain network oscillations during seizures in drug-naïve patients with juvenile absence epilepsy.

Objective: We aimed to investigate the brain network activity during seizures in patients with untreated juvenile absence epilepsy. Methods: Thirty-six juvenile absence epilepsy (JAE) patients with a current high frequency of seizures (more than five seizures during a 2 h EEG examination) were included. Each participant underwent a 2 h video EEG examination. Five 10 s EEG epochs for inter-ictal, pre-ictal, and post-ictal, and five 5 s EEG epochs for ictal states were extracted. Five 10 s resting-state EEG epochs for each participant from a sex- and age-matched healthy control (HC) were enrolled. The topological parameters of the brain networks were calculated using a graph theory analysis. Results: Compared with the resting state of the HC group, the global efficiency, local efficiency, and clustering coefficients of the JAE group decreased in the inter-ictal state. In addition, the ictal state showed significantly increased global and local efficiency and clustering coefficients (p < 0.05) and a decreased small-world index and the shortest path length (p < 0.05) in the theta and alpha bands, compared to the remaining states within the JAE group. Moreover, subgroup analysis revealed that those JAE patients with typical 3 Hz discharges had upgraded global efficiency, local efficiency, and clustering coefficients in both delta and beta1 bands, compared to those JAE patients with non-3 Hz discharges during seizures. Conclusion: The present study supported the idea that the changes in the EEG brain networks in JAE patients are characterized by decreased global and local efficiency and clustering coefficient in the alpha band. Moreover, the onset of seizures is accompanied by excessively enhanced network efficiency. JAE patients with different ictal discharge patterns may have different functional network oscillations.

Stroke Related Brain-Heart Crosstalk: Pathophysiology, Clinical Implications, and Underlying Mechanisms.

The emergence of acute ischemic stroke (AIS) induced cardiovascular dysfunctions as a bidirectional interaction has gained paramount importance in understanding the intricate relationship between the brain and heart. Post AIS, the ensuing cardiovascular dysfunctions encompass a spectrum of complications, including heart attack, congestive heart failure, systolic or diastolic dysfunction, arrhythmias, electrocardiographic anomalies, hemodynamic instability, cardiac arrest, among others, all of which are correlated with adverse outcomes and mortality. Mounting evidence underscores the intimate crosstalk between the heart and the brain, facilitated by intricate physiological and neurohumoral complex networks. The primary pathophysiological mechanisms contributing to these severe cardiac complications involve the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic and parasympathetic hyperactivity, immune and inflammatory responses, and gut dysbiosis, collectively shaping the stroke-related brain-heart axis. Ongoing research endeavors are concentrated on devising strategies to prevent AIS-induced cardiovascular dysfunctions. Notably, labetalol, nicardipine, and nitroprusside are recommended for hypertension control, while ß-blockers are employed to avert chronic remodeling and address arrhythmias. However, despite these therapeutic interventions, therapeutic targets remain elusive, necessitating further investigations into this complex challenge. This review aims to delineate the state-of-the-art pathophysiological mechanisms in AIS through preclinical and clinical research, unraveling their intricate interplay within the brain-heart axis, and offering pragmatic suggestions for managing AIS-induced cardiovascular dysfunctions.

Zhilong Huoxue Tongyu capsule attenuates intracerebral hemorrhage induced redox imbalance by modulation of Nrf2 signaling pathway.

Background: One of the severely debilitating and fatal subtypes of hemorrhagic stroke is intracerebral hemorrhage (ICH), which lacks an adequate cure at present. The Zhilong Huoxue Tongyu (ZLHXTY) capsule has been utilized effectively since last decade to treat ICH, in some provinces of China but the scientific basis for its mechanism is lacking. Purpose: To investigate the neuroprotective role of ZLHXTY capsules for ICH-induced oxidative injury through the regulation of redox imbalance with the Nrf2 signaling pathway. Methods: Autologous blood injection model of ICH in C57BL/6J mice was employed. Three treatment groups received ZLHXTY once daily through oral gavage at doses 0.35 g/kg, 0.7 g/kg, and 1.4 g/kg, started after 2 h and continued for 72 h of ICH induction. The neurological outcome was measured using a balance beam test. Serum was tested for inflammatory markers IL-1ß, IL-6, and TNF-α through ELISA, oxidative stress through hydrogen peroxide content assay, and antioxidant status by total antioxidant capacity (T-AOC) assay. Nuclear extract from brain tissue was assayed for Nrf2 transcriptional factor activity. RT-qPCR was performed for Nfe2l2, Sod1, Hmox1, Nqo1, and Mgst1; and Western blotting for determination of protein expression of Nrf2, p62, Pp62, Keap, HO1, and NQO1. Fluoro-jade C staining was also used to examine neuronal damage. Results: ZLHXTY capsule treatment following ICH demonstrated a protective effect against oxidative brain injury. Neurological scoring showed improvement in behavioral outcomes. ELISA-based identification demonstrated a significant decline in the expression of serum inflammatory markers. Hydrogen peroxide content in serum was found to be reduced. The total antioxidant capacity was also reduced in serum, but the ZLHXTY extract showed a concentration-dependent increase in T-AOC speculating at its intrinsic antioxidant potential. Nrf2 transcriptional factor activity, mRNA and protein expression analyses revealed normalization of Nrf2 and its downstream targets, which were previously elevated as a result of oxidative stress induced by ICH. Neuronal damage was also reduced markedly after ZLHXTY treatment as revealed by Fluoro-jade C staining. Conclusion: ZLHXTY capsules possess an intrinsic antioxidant potential that can modulate the ICH-induced redox imbalance in the brain as revealed by the normalization of Nrf2 and its downstream antioxidant targets.

Glomus Tumors of the Distal Phalanx: A Retrospective Review of Clinical Diagnosis and Treatment.

Glomus tumors (GTs) are rare and typically occur in distal digital bones, with a majority of cases comprising benign vascular tumors. The current study retrospectively reviewed 10 cases of GTs treated by the authors between January 2009 and December 2016. In 9 cases, the GTs were subungual; 1 case was periungual. The affected fingers included 2 thumbs, 3 index fingers, 3 middle fingers, and 2 little fingers. The GTs showed characteristic signs and symptoms. All patients underwent tumor excision. Pathological examination found a thin layer of fibrous membrane surrounding the excised tumor body, which contained small vessels surrounded by multilayered tumor cells. No recurrence was seen during follow-up. The results of this study suggested the following: (1) whole tumor excision is key to preventing GT recurrence; and (2) in case of considerable phalangeal cortex erosion, K-wire fixation followed by autogenous bone grafting can produce satisfactory outcomes, although accurate evidence-based indications for this management need to be established. [Orthopedics. 2022;45(2):e101-e106.].

[Autologous bone marrow integrating artificial bone and ilium periosteum transplantation for treatment of bone nonunion].

OBJECTIVE: To evaluate the initial clinical effect of the autologous bone marrow integrating artificial bone and ilium periosteum transplantation in treatment of problematic nonunion. METHODS: From January 2004 to July 2006, 12 patients (13 limbs)with problematic nonunion were treated with autologous bone marrow integrating artificial bone and ilium periosteum. There were 8 males and 4 females, aged 17-58 years old. The position of nonunion were the tibia in 7 limbs, the femur in 3 limbs, the humerus in 2 limbs. The operated number was 1-4, mean 2.5. The time from injury to therapy was 13 months to 9 years, mean 47.6 months. The bone defect distance was 6-30 mm (mean 15 mm) through 1 : 1 X-rays before operation. Eleven limbs were treated by internal fixation (10 limbs by the bone nail and 1 limb by the limited contact-dynamic compression plate), 2 limbs were treated by the external fixation. The X-ray films were taken at 1 day, 1, 3, 6, 9, 12 months after operation to observe fracture union. RESULTS: All patients were followed up for 12-26 months (mean 17.5 months) and achieved union within 4-7 months (mean 6 months). No deformity of rotation, angulation and crispation occurred in 13 limbs, but functional impairment occurred in 6 limbs after union of fracture. CONCLUSION: Autologous bone marrow integrating artificial bone and ilium periosteum transplantation for treatment of problematic nonunion has the satisfactory result.