Synergistic Effect of Hyperactive Antifreeze Protein on Inhibition of Gas-Hydrate Growth by Hydrophobic and Hydrophilic Groups.

Antifreeze proteins (AFPs) are biodegradable inhibitors that effectively prevent the formation of natural gas hydrates that block pipelines. In this study, molecular dynamics simulations were employed to establish a kinetic model of the hyperactive insect antifreeze protein (Tenebrio molitor, TmAFP) and its mutants to inhibit the growth of sI natural methane hydrate. Simulations revealed that the hydrophobic and hydrophilic groups of threonine (Thr) residues at hydrate-binding sites played a synergistic role in binding hydrates. The hydrophobic groups anchored TmAFP to the hydrate surface through residues Thr39-Thr65 by migrating pendant hydrophobic methyl groups to the hydrate semicages. The hydrophilic groups stabilized TmAFP by hydrogen bonding with water molecules and integrating them into a quasi-hydrate structure, which more effectively inhibited hydrate growth. The results suggest that the hydrate growth inhibition is attributed to both the shape complementarity and the flexibility of binding residues. The synergy between hydrophobic and hydrophilic groups provides guidance for the design of more effective hydrate inhibitors.

MiR-137 promotes TLR4/NF-κB pathway activity through targeting KDM4A, inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells and aggravates osteoporosis.

PURPOSE: As the global population ages rapidly, osteoporotic fractures have become an important public health problem. Previous studies have suggested that miR-137 is involved in the regulation of bone formation, but its specific regulatory mechanism remains unclear. In this study, we aimed to explore the expression, role, and regulatory mechanism of miR-137 in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). METHODS: hBMSCs were induced into osteoblasts at first, and the expression level of miR-137 at different time points was detected. After knockdown and overexpression of miR-137, the effect of miR-137 on the osteogenic differentiation of hBMSCs was examined through alkaline phosphatase (ALP) staining and Alizarin Red staining. Western blotting was performed to detect the expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. Bioinformatics websites were used to predict the target binding sites for miR-137 and KDM4A, and the results were validated using luciferase reporter gene experiments. Moreover, the ALP activity, calcium nodule formation, and activation of Runx2, OCN, and TLR4/NF-κB pathways were observed after knockdown of KDM4A. RESULTS: The expression of miR-137 decreased during osteogenic differentiation. Knockdown of miR-137 expression increased the osteogenic ability of hBMSCs, while overexpression of it weakened the ability. Through the activation of the TLR4/NF-κB pathway, miR-137 inhibited osteogenic differentiation. KDM4A was identified as a predicted target gene of miR-137. After knocking down KDM4A expression, the osteogenic ability of hBMSCs was diminished, and the TLR4/NF-κB pathway was activated. Furthermore, the osteogenic ability of hBMSCs was partially restored and the activation level of TLR4/NF-κB was reduced after miR-137 knockdown. CONCLUSION: MiR-137 enhances the activity of the TLR4/NF-κB pathway by targeting KDM4A, thereby inhibiting the osteogenic differentiation of hBMSCs and exacerbating osteoporosis.

Natural mineral fibers: conducting inhalation toxicology studies-part B: development of a nose-only exposure system for repeat-exposure in vivo study of Libby amphibole aerosol.

BACKGROUND: Exposure to asbestos is associated with malignant and nonmalignant respiratory disease. To strengthen the scientific basis for risk assessment on fibers, the National Institute of Environmental Health Sciences (NIEHS) has initiated a series of studies to address fundamental questions on the toxicology of naturally occurring asbestos and related mineral fibers after inhalation exposure. A prototype nose-only exposure system was previously developed and validated. The prototype system was expanded to a large-scale exposure system in this study for conducting subsequent in vivo rodent inhalation studies of Libby amphibole (LA) 2007, selected as a model fiber. RESULTS: The exposure system consisting of six exposure carousels was able to independently deliver stable LA 2007 aerosol to individual carousels at target concentrations of 0 (control group), 0.1, 0.3, 1, 3, or 10 mg/m3. A single aerosol generator was used to provide aerosol to all carousels to ensure that exposure atmospheres were chemically and physically similar, with aerosol concentration as the only major variable among the carousels. Transmission electron microscopy (TEM) coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis of aerosol samples collected at the exposure ports indicated the fiber dimensions, chemical composition, and mineralogy were equivalent across exposure carousels and were comparable to the bulk LA 2007 material. CONCLUSION: The exposure system developed is ready for use in conducting nose-only inhalation toxicity studies of LA 2007 in rats. The exposure system is anticipated to have applicability for the inhalation toxicity evaluation of other natural mineral fibers of concern.

Natural mineral fibers: conducting inhalation toxicology studies - part A: Libby Amphibole aerosol generation and characterization method development.

BACKGROUND: Asbestos has been classified as a human carcinogen, and exposure may increase the risk of diseases associated with impaired respiratory function. As the range of health effects and airborne concentrations that result in health effects across asbestos-related natural mineral fiber types are not fully understood, the National Institute of Environmental Health Sciences has established a series of research studies to characterize hazards of natural mineral fibers after inhalation exposure. This paper presents the method development work of this research project. RESULTS: A prototype nose-only exposure system was fabricated to explore the feasibility of generating natural mineral fiber aerosol for in vivo inhalation toxicity studies. The prototype system consisted of a slide bar aerosol generator, a distribution/delivery system and an exposure carousel. Characterization tests conducted using Libby Amphibole 2007 (LA 2007) demonstrated the prototype system delivered stable and controllable aerosol concentration to the exposure carousel. Transmission electron microscopy (TEM) analysis of aerosol samples collected at the exposure port showed the average fiber length and width were comparable to the bulk LA 2007. TEM coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis further confirmed fibers from the aerosol samples were consistent with the bulk LA 2007 chemically and physically. CONCLUSIONS: Characterization of the prototype system demonstrated feasibility of generating LA 2007 fiber aerosols appropriate for in vivo inhalation toxicity studies. The methods developed in this study are suitable to apply to a multiple-carousel exposure system for a rat inhalation toxicity testing using LA 2007.

Decreased SPTBN2 expression regulated by the ceRNA network is associated with poor prognosis and immune infiltration in low­grade glioma.

The majority of low-grade gliomas (LGGs) in adults invariably progress to glioblastoma over time. Spectrin ß non-erythrocytic 2 (SPTBN2) is detected in numerous tumors and is involved in tumor occurrence and metastasis. However, the specific roles and detailed mechanisms of SPTBN2 in LGG are largely unknown. The present study performed pan-cancer analysis for the expression and prognosis of SPTBN2 in LGG using The Cancer Genome Atlas and The Genotype-Tissue Expression. Western blotting was used to detect the amount of SPTBN2 between glioma tissues and normal brain tissues. Subsequently, based on expression, prognosis, correlation and immune infiltration, non-coding RNAs (ncRNAs) were identified that regulated SPTBN2 expression. Finally, tumor immune infiltrates associated with SPTBN2 and prognosis were performed. Lower expression of SPTBN2 was correlated with an unfavorable outcome in LGG. A significant correlation between the low SPTBN2 mRNA expression and poor clinicopathological features was observed, including wild-type isocitrate dehydrogenase status (P<0.001), 1p/19q non-codeletion (P<0.001) and elders (P=0.019). The western blotting results revealed that, compared with normal brain tissues, the amount of SPTBN2 was significantly lower in LGG tissues (P=0.0266). Higher expression of five microRNAs (miRs/miRNAs), including hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-34c-5p and hsa-miR-424-5p, correlated with poor prognosis by targeting SPTBN2 in LGG. Subsequently, four long ncRNAs (lncRNAs) [ARMCX5-GPRASP2, BASP1-antisense RNA 1 (AS1), EPB41L4A-AS1 and LINC00641] were observed in the regulation of SPTBN2 via five miRNAs. Moreover, the expression of SPTBN2 was significantly correlated with tumor immune infiltration, immune checkpoint expression and biomarkers of immune cells. In conclusion, SPTBN2 was lowly expressed and correlated with an unfavorable prognosis in LGG. A total of six miRNAs and four lncRNAs were identified as being able to modulate SPTBN2 in a lncRNA-miRNA-mRNA network of LGG. Furthermore, the current findings also indicated that SPTBN2 possessed anti-tumor roles by regulating tumor immune infiltration and immune checkpoint expression.

Correction: Zhang et al. Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis. Brain Sci. 2022, 12, 1183.

We would like to submit the following corrections to our recently published paper [...].

Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis.

This study aimed to investigate the association between serum iron (SI) and postoperative delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively analyzed 985 consecutive adult patients diagnosed with aSAH. Demographic, clinical, and laboratory data were recorded. Univariate and multivariate analyses were employed to assess the association between SI and DCI. Propensity-score matching (PSM) analysis was implemented to reduce confounding. Postoperative DCI developed in 14.38% of patients. Lower SI upon admission was detected in aSAH patients with severe clinical conditions and severe aSAH. SI was negatively correlated with WFNS grade (r = −0.3744, p < 0.001) and modified Fisher (mFisher) grade (r = −0.2520, p < 0.001). Multivariable analysis revealed lower SI was independently associated with DCI [odds ratios (OR) 0.281, 95% confidence interval (CI) 0.177−0.448, p < 0.001], while WFNS grade and mFisher grade were not. The receiver-operating characteristics (ROC) curve analysis of SI for DCI gave an area under the curve (AUC) of 0.7 and an optimal cut-off of 7.5 µmol/L (95% CI 0.665 to 0.733, p < 0.0001). PSM demonstrated the DCI group had a significantly lower SI than the non-DCI group (10.91 ± 6.86 vs. 20.34 ± 8.01 µmol/L, p < 0.001). Lower SI remained a significant independent predictor for DCI and an independent poor prognostic factor of aSAH in multivariate analysis (OR 0.363, 95% CI 0.209−0.630, p < 0.001). The predictive performance of SI for poor outcome had a corresponding AUC of 0.718 after PSM. Lower SI upon admission is significantly associated with WFNS grade, mFisher grade, and predicts postoperative DCI and poor outcome at 90 days following aSAH.

Elevated Hexose-6-Phosphate Dehydrogenase Regulated by OSMR-AS1/hsa-miR-516b-5p Axis Correlates with Poor Prognosis and Dendritic Cells Infiltration of Glioblastoma.

Objective Glioblastoma (GBM), a type of malignant glioma, is the most aggressive type of brain tumor and is associated with high mortality. Hexose-6-phosphate dehydrogenase (H6PD) has been detected in multiple tumors and is involved in tumor initiation and progression. However, the specific role and mechanism of H6PD in GBM remain unclear. Methods We performed pan-cancer analysis of expression and prognosis of H6PD in GBM using the Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Subsequently, noncoding RNAs regulating H6PD expression were obtained by comprehensive analysis, including gene expression, prognosis, correlation, and immune infiltration. Finally, tumor immune infiltrates related to H6PD and survival were performed. Results Higher expression of H6PD was statistically significantly associated with an unfavorable outcome in GBM. Downregulation of hsa-miR-124-3p and hsa-miR-516b-5p in GBM was detected from GSE90603. Subsequently, OSMR-AS1 was observed in the regulation of H6PD via hsa-miR-516b-5p. Moreover, higher H6PD expression significantly correlated with immune infiltration of dendritic cells, immune checkpoint expression, and biomarkers of dendritic cells. Conclusions The OSMR-AS1/ miR-516b-5p axis was identified as the highest-potential upstream ncRNA-related pathway of H6PD in GBM. Furthermore, the present findings demonstrated that H6PD blockading might possess antitumor roles via regulating dendritic cell infiltration and immune checkpoint expression.

Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury.

BACKGROUND: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus result in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first-order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. METHODS: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC glutamatergic neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling. RESULTS: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC glutamatergic neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. CONCLUSIONS: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.

Clinical Characteristics of Hydrocephalus Following the Treatment of Pyogenic Ventriculitis Caused by Multi/Extensive Drug-Resistant Gram-Negative Bacilli, Acinetobacter Baumannii, and Klebsiella Pneumoniae.

Objective: Hydrocephalus is common after ventriculitis. This study explores hydrocephalus's clinical characteristics following pyogenic ventriculitis due to multidrug-resistant and extensively drug-resistant Acinetobacter baumannii and Klebsiella pneumoniae. Patients and Methods: We retrospectively reviewed patients with post-neurosurgical pyogenic ventriculitis due to multidrug-resistant and extensively drug-resistant A. baumannii and K. pneumoniae in our department between January 2014 and June 2020. Once diagnosed, patients received intraventricular lavage followed by daily intraventricular administration of Colistin (polymyxin-E). The patient's clinical/radiographic findings were analyzed and evaluated 6 months after discharge. Results: In total, 48 cases were included in this study, and 25% were female. The median age was 45 (SD ± 15) years old. Median intraventricular Colistin administration to acquire sterile cerebrospinal fluid (CSF) was 20 days. Forty-one patients developed hydrocephalus; among them, 18 (43%) had multiloculated hydrocephalus (MLH), 23 (56%) had uni/non-loculated hydrocephalus (ULH/NLH), and 7 (17%) did not develop hydrocephalus. The patients with MLH had (15 days) delayed initiation of intraventricular irrigation (p < 0.022). They had (32 days) longer intraventricular Colistin (p < 0.003) and showed worse outcomes in terms of Glasgow outcome score (GOS) at 6 months follow-up than those without hydrocephalus. The mean score of the MLH group was 1.67 (SD1.23), and ULH/NLH was 2.61 (SD1.4) at p < 0.008. Conclusion: Multiloculated hydrocephalus is common in patients receiving delayed intraventricular administration of Colistin and required a longer duration on intraventricular Colistin to treat the pyogenic ventriculitis caused by multidrug/extensive drug-resistant A. baumannii and K. pneumoniae. It is associated with worse clinical outcomes.

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures.

Objective: We test the hypothesis that lysine acetylation is involved in the metabolic process of glioma-associated seizures (GAS). Methods: We used label-free mass spectrometry-based quantitative proteomics to quantify dynamic changes of protein acetylation between gliomas with seizure (CA1 group) and gliomas without seizure (CA2 group). Furthermore, differences of acetyltransferase and deacetylase expression between CA1 and CA2 groups were performed by a quantitative proteomic study. We further classified acetylated proteins into groups according to cell component, molecular function, and biological process. In addition, metabolic pathways and protein interaction networks were analyzed. Regulated acetyltransferases and acetylated profiles were validated by PRM and Western blot. Results: We detected 169 downregulated lysine acetylation sites of 134 proteins and 39 upregulated lysine acetylation sites of 35 proteins in glioma with seizures based on acetylome. We detected 407 regulated proteins by proteomics, from which ACAT2 and ACAA2 were the differentially regulated enzymes in the acetylation of GAS. According to the KEGG analysis, the upregulated acetylated proteins within the PPIs were mapped to pathways involved in the TCA cycle, oxidative phosphorylation, biosynthesis of amino acids, and carbon metabolism. The downregulated acetylated proteins within the PPIs were mapped to pathways involved in fatty acid metabolism, oxidative phosphorylation, TCA cycle, and necroptosis. Regulated ACAT2 expression and acetylated profiles were validated by PRM and Western blot. Conclusions: The data support the hypothesis that regulated protein acetylation is involved in the metabolic process of GAS, which may be induced by acetyl-CoA acetyltransferases.

Downregulation of MCM8 expression restrains the malignant progression of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor with an extremely poor prognosis. Minichromosome maintenance 8 homologous recombination repair factor (MCM8) is a helicase involved in the elongation step of DNA replication and tumorigenesis. In the present study, the clinical significance and biological function of MCM8 in CCA were investigated. The expression levels of MCM8 in CCA and paracancerous tissues were analyzed using immunohistochemical staining. The potential mechanisms underlying MCM8 and the biological effects of MCM8 in CCA cells were explored using in vitro assays and in vivo mouse xenograft models. The high expression levels of MCM8 in CCA has important clinical significance in predicting disease progression. Knockdown of MCM8 decreased proliferation, promoted apoptosis and suppressed migration of CCA cells. MCM8 knockdown also suppressed tumor growth in vivo. Mechanistically, MCM8 knockdown led to the abnormal downregulation of survivin, XIAP, HSP27, IGF­1sR, sTNF­R1, sTNF­R2, TNF­α and TNF­ß. Furthermore, downregulation of MCM8 expression inhibited the PI3K/Akt signaling pathway and induced the MAPK9 signaling pathway. MCM8 promoted the malignant progression of CCA, indicating that inhibition of MCM8 may have the potential to serve as a novel molecular targeted therapy.

9-Bromo-2,3-diethylbenzo[de]chromene-7,8-dione (MSN54): A novel non-intercalative topoisomerase II catalytic inhibitor.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.

Structure and function of corticospinal projection originating from supplementary motor area.

PURPOSE: The importance of supplementary motor area (SMA) for motor function and compensation for primary motor area (M1) has received increased attention. METHODS: We used diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS) to evaluate structure and function of corticospinal projection originating from SMA. Fibers of corticospinal projection originating from M1 (CST) and SMA (ACST) were analyzed. ACST originating from mesial SMA area formed separate white matter bundles leaving the anterior part of M1 area, which then entered the posterior limb of the internal capsule. Projection and overlap of both CST and ACST were detected on medulla. RESULTS: Fibers of contralesional ACST were more than that of ipsilesional ACST in patients with SMA tumors (p<0.05). In patients with SMA tumor, all patients experienced temporary akinesia postoperatively. Seven hundred forty-one fibers of ipsilateral ACST and no fibers of ipsilateral CST were detected in the patient with M1 glioma, while most of contralateral limb movement was preserved. MEP could be evoked by stimulating SMA area as well as M1 area. ACST originated from SMA area and projected to the medial medulla. CONCLUSION: SMA area and ACST integrity contributed to contralateral motor function and were a compensation for M1 lesion and damaged CST.

Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats.

Antineoplastic drugs such as oxaliplatin (OXA) often induce memory and emotional deficits. At present, the mechanisms underlying these side-effects are not fully understood, and no effective treatment is available. Here, we show that the short-term memory deficits and anxiety-like and depression-like behaviors induced by intraperitoneal injections of OXA (4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-D-aspartate receptors in the hippocampus, which is critically involved in memory and emotion. The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate (L-TAMS, 604 mg/kg per day, from 2 days before until the end of experiments). We found that OXA injections significantly reduced the free Mg2+ in serum and cerebrospinal fluid (from ~ 0.8 mmol/L to ~ 0.6 mmol/L). The Mg2+ deficiency (0.6 mmol/L) upregulated tumor necrosis factor (TNF-α) and phospho-p65 (p-p65), an active form of nuclear factor-kappaB (NF-κB), and downregulated the NR2B subunit in cultured hippocampal slices. Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65, as well as microglial activation in the hippocampus and the medial prefrontal cortex. Finally, similar to oral L-TAMS, intracerebroventricular injection of PDTC, an NF-κB inhibitor, also prevented the OXA-induced memory/emotional deficits and the changes in TNF-α, p-p65, and microglia. Taken together, the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg2+ is responsible for the memory/emotional deficits induced by OXA. Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.

Design, synthesis and biological evaluation of novel perimidine o-quinone derivatives as non-intercalative topoisomerase II catalytic inhibitors.

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 µM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 µM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 µM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.

Lower Serum Iron and Hemoglobin Levels are Associated with Acute Seizures in Patients with Ruptured Cerebral Aneurysms.

BACKGROUND AND OBJECTIVE: The aim of the study is to investigate the value of serum iron and hemoglobin levels for predicting acute seizures following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Clinical and laboratorial data from patients with ruptured intracranial aneurysms were collected in the retrospective study. Age, sex, symptom onset, history of diabetes and hypertension, history of coronary artery disease, temperature, Hunt-Hess grade, Fisher grade, aneurysm location, hemoglobin, serum potassium, sodium, calcium, phosphorus, and iron were collected. Acute seizures were determined as seizures within 1 week following aSAH. Propensity score matching (PSM) analyses were performed to correct imbalances in patient characteristics between seizure and non-seizure groups. RESULTS: A total of 760 patients were included. Incidence of acute seizures following aSAH was 6.4%. In the univariate analysis, significant differences were detected in age, admission Hunt-Hess grade, Fisher grade, hemoglobin, serum sodium, and serum iron between seizure and non-seizure groups. In multivariate logistic regression model, lower serum iron was considered as a risk factor for acute seizures (OR 0.182, 95% CI 0.084-0.393, p = 0.000), as well as lower hemoglobin (OR 0.977, 95% CI 0.962-0.993, p = 0.004) and higher serum sodium (OR 1.072, 95% CI 1.003-1.145, p = 0.039). After PSM, there were no significant differences in age, admission Hunt-Hess grade, Fisher grade, and serum sodium between seizure and non-seizure groups. The matched seizure group had lower serum iron and hemoglobin levels compared with the matched non-seizure group (p < 0.05). The optimal cutoff value for serum iron and hemoglobin levels as a predictor of acute seizure after aSAH was determined as 9.9 mmol/L (sensitivity was 81.63% and the specificity was 65.40%) and 119 g/L (sensitivity was 63.27% and the specificity was 70.18%), respectively. CONCLUSIONS: Serum iron and hemoglobin levels were inversely associated with a high risk of acute seizures following aSAH.

Network pharmacology-based identification for therapeutic mechanism of Ling-Gui-Zhu-Gan decoction in the metabolic syndrome induced by antipsychotic drugs.

BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.

Cerebellopontine Angle Tumors Are Associated with a Greater Incidence of Unruptured Intracranial Aneurysms.

OBJECTIVE: We tested the hypothesis that cerebellopontine angle (CPA) tumors are associated with a greater incidence of unruptured intracranial aneurysms (IAs). METHODS: Patients with intracranial tumors (ITs) undergoing computed tomography angiography and magnetic resonance imaging were enrolled in an observational cohort study that prospectively collected age, sex, hypertension, diabetes, cerebral arteriosclerosis, tumor type, tumor location, hydrocephalus, smoking, alcohol intake, CPA tumor size, cerebral aneurysms, and cerebral arteriosclerosis. Patients with the coexistence of IA and ITwere classified as group II, whereas the others with IT as group I. RESULTS: We included 1218 patients with IT for analysis. The incidence of IA was 7.1% (86/1218). A total of 31% of patients with aneurysms had CPA tumors. In a multivariate logistic regression model, a greater incidence of IA was found in female patients (odds ratio [OR] 1.726, 95% confidence interval [CI] 1.050-2.836, P=0.031) and in patients with CPA tumors (OR 3.002, 95% CI 1.822-4.947, P=0.000) after adjustment for tumor type, cerebral arteriosclerosis, and age. In female patients, CPA tumors were a unique independent risk factor of a greater incidence of IA (OR 2.270, 95% CI 1.194-4.317, P=0.012). Furthermore, cerebral arteriosclerosis was a unique independent risk factor of IA in patients with CPA tumors (OR 7.626, 95% CI 2.928-19.860, P=0.000). CONCLUSIONS: These data support the hypothesis that CPA tumors are associated with a greater incidence of unruptured IAs, especially in female patients. Cerebral arteriosclerosis contributed to elevated risk of IA in patients with CPA tumors.