Meta-analysis of MMP-9 levels in the serum of patients with epilepsy

BackgroundEpilepsy’s pathogenesis and progression are significantly influenced by neuroinflammation, blood–brain barrier function, and synaptic remodeling function. Matrix metalloproteinase 9 (MMP-9), as a critical factor, may contribute to the development of epilepsy through one or more of the above-mentioned pathways. This study aims to evaluate and quantify the correlation between MMP-9 levels and epilepsy.MethodsWe conducted a comprehensive search of Embase, Web of Science, PubMed, Cochrane Library, WanFang DATA, VIP, and the CNKI to identify studies that investigate the potential association between MMP-9 and epilepsy. The data were independently extracted by two researchers and assessed for quality using the Cochrane Collaboration tool. The extracted data were analyzed using Stata 15 and Review Manager 5.4. The study protocol was registered prospectively at PROSPERO, ID: CRD42023468493.ResultsThirteen studies with a total of 756 patients and 611 matched controls met the inclusion criteria. Eight of these studies reported total serum MMP-9 levels, and the other five studies were used for a further subgroup analysis. The meta-analysis indicated that the serum MMP-9 level was higher in epilepsy patients (SMD = 4.18, 95% confidence interval = 2.18–6.17, p < 0.00001) compared with that in the control group. Publication bias was not detected according to Begg’s test. The subgroup analysis of country indicated that the epilepsy patients in China, Poland, and Egypt had higher levels of serum MMP-9 than the control group, with the increase being more pronounced in Egypt. The subgroup analysis of the age category demonstrated that the serum MMP-9 levels of the adult patients with epilepsy were significantly higher than those of the matched controls. However, the serum MMP-9 levels did not significantly differ in children with epilepsy. The subgroup analysis of the seizure types demonstrated substantial difference in the MMP-9 levels between patients of seizure-free epilepsy (patients who have been seizure-free for at least 7 days) and the control group. Meanwhile, the serum MMP-9 level in patients with epileptic seizures was significantly higher than that in the control group. The subgroup analysis based on seizure duration in patients showed that the serum MMP-9 levels at 1–3, 24, and 72 h after seizure did not exhibit significant differences between female and male patients with epilepsy when compared with the control group. The serum MMP-9 levels at 1–3 and 24 h were significantly higher than those of the matched controls. Nevertheless, the serum MMP-9 level at 72 h was not significantly different from that in the control group.ConclusionThis meta-analysis presents the first comprehensive summary of the connection between serum MMP-9 level and epilepsy. The MMP-9 levels in epilepsy patients are elevated. Large-scale studies with a high level of evidence are necessary to determine the exact relationship between MMP-9 and epilepsy

Mechanistic study of endothelium independent vasodilation effects of wogonin

34-40Scutellaria baicalensis Georgi, locally known as HuangQin, and commonly as Baikal or Chinese skullcap, is an important herb in Chinese traditional medicine. The flavonoids from this plant are main active substances responsible for its medicinal applications. Wogonin is one such active ingredient derived from this plant. Here, we investigated the mechanism of the vasodilation effect of wogonin on isolated rat thoracic aortas. For this study, endothelium intact and endothelium removed thoracic aortic rings were prepared from rats. Using a tension transducer, the tension of the rat thoracic aortic rings was recorded. Results showed that wogonin is able to relax the endothelium-intact aortic rings, but L-NAME, indomethacin (Indo), and methylene blue (MB) could not reduce the tension in these rings. Wogonin was also able to relax endotheliumremoved rings. However, treatment with tetraethylammonium (TEA), BaCl2, glibenclamide (Gly), 4-aminopyridine (4-AP), and verapamil (Ver) had no effect on vasodilation induced by wogonin. Using wogonin to pre-treat endothelium-removed aortic rings reduced the contraction induced by K+. Pre-treatment of endothelium-removed aortic rings with wogonin markedly reduced the contraction induced by 10-6 M PE in Ca2+-free solution. It could be concluded that L-type calcium channels and intracellular Ca2+ release is inhibited by wogonin

Mechanistic study of endothelium independent vasodilation effects of wogonin

Scutellaria baicalensis Georgi, locally known as HuangQin, and commonly as Baikal or Chinese skullcap, is an important herb in Chinese traditional medicine. The flavonoids from this plant are main active substances responsible for its medicinal applications. Wogonin is one such active ingredient derived from this plant. Here, we investigated the mechanism of the vasodilation effect of wogonin on isolated rat thoracic aortas. For this study, endothelium intact and endothelium removed thoracic aortic rings were prepared from rats. Using a tension transducer, the tension of the rat thoracic aortic rings was recorded. Results showed that wogonin is able to relax the endothelium-intact aortic rings, but L-NAME, indomethacin (Indo), and methylene blue (MB) could not reduce the tension in these rings. Wogonin was also able to relax endotheliumremoved rings. However, treatment with tetraethylammonium (TEA), BaCl2, glibenclamide (Gly), 4-aminopyridine (4-AP), and verapamil (Ver) had no effect on vasodilation induced by wogonin. Using wogonin to pre-treat endothelium-removed aortic rings reduced the contraction induced by K+. Pre-treatment of endothelium-removed aortic rings with wogonin markedly reduced the contraction induced by 10-6 M PE in Ca2+-free solution. It could be concluded that L-type calcium channels and intracellular Ca2+ release is inhibited by wogonin

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study

Myelodysplastic syndrome (MDS) with TP53 mutations has a poor prognosis after transplantation, and novel therapeutic means are urgently needed. Decitabine (Dec) monotherapy has demonstrated improved overall response rates in MDS and acute myeloid leukaemia, although these responses were not durable. This study aimed to preliminary evaluate the efficacy of a Dec-containing allogeneic haematopoietic stem cell transplantation (allo-HSCT) preconditioning regimen in TP53-mutant MDS. Nine patients with TP53-mutant myelodysplastic syndromes received the decitabine-containing preconditioning regimen and subsequent myeloablative allo-HCT between April 2013 and September 2021 in different centres. At a median follow-up of 42 months (range, 5 to 61 months), the overall survival (OS) was 89% (8/9), progression-free survival (PFS) was 89% (8/9), and relapse incidence was 11.1%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 22.2% (2/9) and that of chronic moderate-to-severe GVHD was 11.1% (1/9). The 1-year GVHD-free/relapse-free survival (GRFS) was 56% (5/9). In conclusion, we found real-world clinical data that supports the use of a Dec-containing preconditioning regimen before allo-HSCT for possible improved outcomes in TP53-mutant MDS patients; there is therefore an urgent call for an in-depth exploration of the involved mechanism to confirm these preliminary findings

Integrative omics reveals rapidly evolving regulatory sequences driving primate brain evolution

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease

Exploring the Coenzyme A Biosynthetic Pathway as Novel Antibiotic Target.

Coenzyme A (CoA) is an essential molecule for all organisms. CoA is biosynthesized via five enzymatic steps from the metabolic precursor pantothenate. Phosphopantetheine, the product of the first three enzymatic steps, is ultimately attached to apo-acyl carrier proteins (ACP) to generate active, holo-ACP, which is reported to participate in up to 13% of all characterized biochemical reactions including essential steps in fatty acid metabolism. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of CoA biosynthesis. PPCS from Enterococcus faecalis and human were cloned, purified, and characterized. While PPCS from both species exhibited similar ordered Bi Uni Uni Bi Ping Pong mechanisms, significant differences in substrate selectivity were found between the bacterial and human PPCS homologues. E. faecalis PPCS was CTP-specific, while human PPCS could use both ATP and CTP in addition to being able to bind UTP and GTP. The CTP specificity of E. faecalis and other bacterial PPCS contrasted with the lack of nucleotide specificity of human PPCS suggests that selective inhibition of bacterial PPCS as a potential anti-bacterial should be feasible. A high throughput screen was conducted against a library of 41,000 small molecules and 11,000 natural product extracts to find novel inhibitors of bacterial PPCS. Several small molecules and natural product extracts were confirmed to be inhibitors of bacterial PPCS, and the inhibition mechanism for one inhibitor was determined. Phosphopantetheine adenylyltransferase (PPAT), the enzyme involved in the fourth step of CoA biosynthesis, was also studied, leveraging the technologies developed in the previous PPCS studies. PPAT from E. faecalis was cloned, purified, and characterized. E. faecalis PPAT was determined to have an ordered Bi Bi mechanism, in contrast to the random Bi Bi mechanism of the previously characterized E. coli PPAT. A high throughput screen to find inhibitors of PPAT was developed, but no specific inhibitors were found in the pilot screen.Ph.D.Medicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/77714/1/jiangwei_1.pd

Mechanisms of Crack Initiation and Propagation in Dense Linear Multihole Directional Hydraulic Fracturing

Artificially fracturing coal-rock mass serves to form break lines therein, which is related to the distribution of cracked boreholes. For this reason, we use physical experiments and numerical simulations to study the crack initiation and propagation characteristics of dense linear multihole drilling of fractured coal-rock mass. The results indicate that only in the area between the first and last boreholes can hydraulic fracturing be controlled by dense linear multihole expansion along the direction of the borehole line; in addition, no directional fracturing occurs outside the drilling section. Upon increasing parameters such as the included angle θ between the drilling arrangement line and the maximum principal stress σ1 direction, the drilling spacing D, the difference Δσ in principal stress, etc., the effect of directional fracture is gradually weakened, and the hydraulic fractures reveal three typical cracking modes: cracking along the borehole line, bidirectional cracking (along the borehole line and perpendicular to the minimum principal stress σ3), and cracking perpendicular to σ3. Five propagation modes also appear in sequence: propagating along borehole line, step-like propagation, S-shaped propagation, bidirectional propagation (along the borehole line and perpendicular to σ3), and propagation perpendicular to σ3. Based on these results, we report the typical characteristics of three-dimensional crack propagation and discuss the influence of the gradient of pore water pressure. The results show clearly that crack initiation and propagation are affected by both the geostress field and the pore water pressure. The pore water pressure will exhibit a circular-local contact-to-integral process during crack initiation and expansion. When multiple cracks approach, the superposition of pore water pressure at the tip of the two cracks increases the damage to the coal rock, which causes crack reorientation and intersection

Meta-analysis of Randomized Controlled Trials of Chinese Herbal Compound inthe Treatment of Diabetes Mellitus Complicated with Insomnia

Objective To systematically evaluate the clinical efficacy and safety of Chinese herbal compound in the treatment of diabetes with insomnia in a randomized controlled trial. Methods The medical databases CNKI,VIP,Wanfang,PubMed,EMBase,and The Cochrane Library were searched to collect and evaluate randomized controlled trial studies that met the inclusion criteria as of February 2023,and relevant data were extracted and analyzed according to outcome measures such as treatment response rate,Pittsburgh sleep quality index(PSQI) scale score,fasting plasma glucose(FPG),hemoglobin A1c(HbA1c),and 2 h postprandial blood glucose(2hPBG). Meta-analysis was performed using Review Manager 5.4 software. Results Thirteen articles met the criteria,and a total of 1 183 cases were included,including 599 cases in the experimental group and 584 cases in the control group.Meta-analysis showed that the treatment response rate,PSQI scale score,FPG,HbA1c and 2hPBG levels in the Chinese herbal compound group were better than those in the Western medicine control group after intervening diabetic patients with insomnia. Conclusion Meta-analysis results suggest that Chinese herbal compound is superior to western medicine in improving diabetes with insomnia