Emerging Role of Ferroptosis in the Pathogenesis of Ischemic Stroke: A New Therapeutic Target?

Ischemic stroke is one of the main causes of high morbidity, mortality, and disability worldwide; however, the treatment methods are limited and do not always achieve satisfactory results. The pathogenesis of ischemic stroke is complex, defined by multiple mechanisms; among them, programmed death of neuronal cells plays a significant role. Ferroptosis is a novel type of regulated cell death characterized by iron redistribution or accumulation and increased lipid peroxidation in the membrane. Ferroptosis is implicated in many pathological conditions, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. In this review, we summarize current research findings on ferroptosis, including possible molecular mechanisms and therapeutic applications of ferroptosis regulators, with a focus on the involvement of ferroptosis in the pathogenesis and treatment of ischemic stroke. Understanding the role of ferroptosis in ischemic stroke will throw some light on the development of methods for diagnosis, treatment, and prevention of this devastating disease.

Constitutive expression of NtabSPL6-1 in tobacco and Arabidopsis could change the structure of leaves and promote the development of trichomes.

The coding sequence of NtabSPL6-1 was cloned by high-fidelity PCR with specific primers and was used in construction of a binary vector for overexpression. Wild-type Col-0 Arabidopsis plants and Qinyan95 tobacco leaves were transformed using floral dip and leaf disc methods, respectively. Phenotypic observation showed that constitutive expression of NtabSPL6-1 in Arabidopsis could promote the development of trichomes on leaf epidermis and influence the growth pattern of cauline leaves. In tobacco, ectopic expression of NtabSPL6-1 led to dwarfism of the plants and alteration of the leaf structure, accompanied by changes of the glandular trichomes in development. At the same time, the self-regulation capability of NtabSPL6-1 was determined by yeast two-hybrid system. The results indicated that SBP-C terminal domain and C terminal domain of NtabSPL6-1 possessed strong transcriptional activation ability; the intact protein, N terminal domain, and the first peptide fragment in N terminal domain possessed weak transcriptional activation ability; and the second and the third peptide fragments in N terminal domain had no transcriptional activation ability, suggesting the N terminal domain of NtabSPL6-1 could block the activity of the C terminal domain. NtabSPL6-1 may affect the resistance of plants to biotic stress factors indirectly by regulation of the trichome growth.

A case report: Becker muscular dystrophy presenting with epilepsy and dysgnosia induced by duplication mutation of Dystrophin gene.

BACKGROUND: Becker muscular dystrophy (BMD), a genetic disorder of X-linked recessive inheritance, typically presents with gradually progressive muscle weakness. The condition is caused by mutations of Dystrophin gene located at Xp21.2. Epilepsy is an infrequent manifestation of BMD, while cases of BMD with dysgnosia are extremely rare. CASE PRESENTATION: We describe a 9-year-old boy with BMD, who presented with epilepsy and dysgnosia. Serum creatine kinase level was markedly elevated (3665 U/L). Wechsler intelligence tests showed a low intelligence quotient (IQ = 65). Electromyogram showed slight myogenic changes and skeletal muscle biopsy revealed muscular dystrophy. Immunohistochemical staining showed partial positivity of sarcolemma for dystrophin-N. Multiplex ligation-dependent probe amplification revealed a duplication mutation in exons 37-44 in the Dystrophin gene. CONCLUSIONS: The present case report helps to better understand the clinical and genetic features of BMD.

Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury.

This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co-administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway.

Neuroprotection by Carbenoxolone Against Ischemia Injury Involves PI3K/Akt Pathway.

BACKGROUND: Previous experimental studies have shown some protective effects on brain ischemic injures in vivo and in vitro models. However, cotreatment with carbenoxolone (Cbx) and phosatidylinositol 3-kinase (PI3K) inhibitor LY 294002 to a focal cerebral ischemia and reperfusion rat model has not been studied yet. Here we investigate their protective effects on neural cells and examine the function of PI3K/Akt pathway in this protection. METHODS: Both flow cytometry and western blot were used quantitatively and qualitatively to determine cell apoptosis. RESULTS: The neural cell apoptosis is related with Cx43, and Bcl-2/Bax and caspase 3 pathways. The percentage of apoptosis cells following transient middle cerebral artery occlusion (MCAO) in mice decrease with the treatment of Cbx. Our data demonstrated that treatment with Cbx reduced cerebral injury in rats exposed to transient focal ischemia and reperfusion (I/R), and this was mediated by the activation of the PI3K/Akt pathways as well as by blocking the caspase 3 apoptosis pathway. LY294002 blocked the increase in phospho-AKT evoked by Cbx and abolished the associated protective effect. CONCLUSIONS: Taken together, these findings provide evidence that Cbx protects neurons against ischemia injury and this neuroprotective effect involves the PI3K/Akt pathway.

Connexin: a potential novel target for protecting the central nervous system?

Connexin subunits are proteins that form gap junction channels, and play an important role in communication between adjacent cells. This review article discusses the function of connexins/hemichannels/gap junctions under physiological conditions, and summarizes the findings regarding the role of connexins/hemichannels/gap junctions in the physiological and pathological mechanisms underlying central nervous system diseases such as brain ischemia, traumatic brain and spinal cord injury, epilepsy, brain and spinal cord tumor, migraine, neuroautoimmune disease, Alzheimer's disease, Parkinson's disease, X-linked Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher-like disease, spastic paraplegia and maxillofacial dysplasia. Connexins are considered to be a potential novel target for protecting the central nervous system.

Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia.

BACKGROUND: The ΔGAG deletion of the TOR1A gene (DYT1) is responsible for DYT1 dystonia. However, no other TOR1A mutation has been reported in the Chinese population. METHODS: Two hundred one dystonia patients without the ΔGAG deletion were screened for other mutations in TOR1A. Gene function changes were analyzed by subcellular distribution and luciferase reporter assay. RESULTS: A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser). Overexpression of mutant TOR1A Asp194Val protein induces inclusion formation in SK-N-AS cell lines, and the repressive activity of the mutant THAP1 Leu180Ser protein on TOR1A gene expression is decreased compared with wild-type THAP1. CONCLUSIONS: This is the first report about a dystonia patient harboring two distinct dystonia gene mutations. Functional analysis indicated a potential additive effect of these two mutations, which might provoke the occurrence of dystonic symptoms in this patient.

Sectional anatomy aid for improvement of decompression surgery approach to vertical segment of facial nerve.

The aim of this study was to find a surgical approach to a vertical segment of the facial nerve (VFN) with a relatively wide visual field and small lesion by studying the location and structure of VFN with cross-sectional anatomy. High-resolution spiral computed tomographic multiplane reformation was used to reform images that were parallel to the Frankfort horizontal plane. To locate the VFN, we measured the distances as follows: from the VFN to the paries posterior bony external acoustic meatus on 5 typical multiplane reformation images, to the promontorium tympani and the root of the tympanic ring on 2 typical images. The mean distances from the VFN to the paries posterior bony external acoustic meatus are as follows: 4.47 mm on images showing the top of the external acoustic meatus, 4.20 mm on images with the best view of the window niche, 3.35 mm on images that show the widest external acoustic meatus, 4.22 mm on images with the inferior margin of the sulcus tympanicus, and 5.49 mm on images that show the bottom of the external acoustic meatus. The VFN is approximately 4.20 mm lateral to the promontorium tympani on images with the best view of the window niche and 4.12 mm lateral to the root of the tympanic ring on images with the inferior margin of the sulcus tympanicus. The other results indicate that the area and depth of the surgical wound from the improved approach would be much smaller than that from the typical approach. The surgical approach to the horizontal segment of the facial nerve through the external acoustic meatus and the tympanic cavity could be improved by grinding off the external acoustic meatus to show the VFN. The VFN can be found by taking the promontorium tympani and tympanic ring as references. This improvement is of high potential to expand the visual field to the facial nerve, remarkably without significant injury to the patients compared with the typical approach through the mastoid process.

Internal carotid artery in the operative plane of endoscopic endonasal transsphenoidal surgery.

The objective of this study was to measure the related parameters of intercarotid artery (ICA) in the operative plane of endonasal transsphenoidal approach for hypophyseal surgeries. Nine parameters of the ICA were examined in the computed tomographic angiographic (CTA) scan of 101 patients. The shortest distance between the middle point of the nasal columella and the projective point of the ICA (D(3)) was 85.50 (5.79) mm. The shortest distance between the anterior wall of the sphenoid sinus and the projective point of the ICA (D(4)) was 16.93 (3.50) mm. The distance between the bilateral projective points of the ICA (D(5)) was 21.60 (3.45) mm. The shortest distance from the anterior wall of the sphenoid sinus to the line between the bilateral projective points of the ICA (D(6)) was 12.1 (3.91) mm. The shortest distance between the middle point of nasal columella and the anterior wall of the sphenoid sinus (D(7)) was 72.67 (5.99) mm. The width of the angle between the bilateral ICA projective point from the middle point of the nasal columella (A(1)) was 14.9 (2.32) degrees. The width of the angle between the bilateral ICA projective points from the anterior-most point of sphenoid sinus (A(2)) was 85.49 (18.12) degrees. Clinically, it is relatively safe to work within the distances and angles measured in this research, and these results may provide information for clinical surgery of pituitary tumor.

Layer I as a putative neurogenic niche in young adult guinea pig cerebrum.

A considerable number of cells expressing typical immature neuronal markers including doublecortin (DCX+) are present around layer II in the cerebral cortex of young and adult guinea pigs and other larger mammals, and their origin and biological implication await further characterization. We show here in young adult guinea pigs that these DCX+ cells are accompanied by in situ cell division around the superficial cortical layers mostly in layer I, but they co-express proliferating cell nuclear antigen (PCNA) and an early neuronal fate determining factor, PAX6. A small number of these DCX+ cells also colocalize with BrdU following administration of this mitotic indicator. Cranial X-ray irradiation causes a decline of DCX+ cells around layer II, and novel environmental exploration induces c-Fos expression among these cells in several neocortical areas. Together, these data are compatible with a notion that DCX+ cortical neurons around layer II might derive from proliferable neuronal precursors around layer I in young adult guinea pig cerebrum, and that these cells might be modulated by experience under physiological conditions.

Use of anthropometric data from the medial tibial and femoral condyles to design unicondylar knee prostheses in the Chinese population.

Anthropometric data on medial tibial condyles and medial femoral condyles of 172 normal knees (94 male knees, 78 female knees) were obtained using three-dimensional computer tomographic measurements. In the medial tibial condyle, we measured the anteroposterior (AP) and widest dimension (WD), and compared the measurements with the similar dimensions of five tibial unicondylar knee prostheses conventionally used in China. In the femur, we used best-fit two-circular arcs to measure the morphology of the sagittal plane of the medial femoral condyle. We found that three of the prostheses showed WD overhang for all ranges of the AP dimension, while two of them showed WD underhang. We also found a progressive decrease in the condylar aspect ratio (WD/AP%) in parallel with an increase in the AP dimension in the medial tibial condyle. However, none of the conventional tibial prosthesis showed a similar change. Furthermore, males had larger values in aspect ratio than females with the same values for AP dimension. There were definite correlations between the radius of the curvature for the posterior part (R1) and distal part (R2) in the sagittal plane of medial femoral condyle. Both of these values were smaller than in the Caucasian population. Both radiuses of curvature for the posterior and distal components showed definite correlations with the AP dimension. The results of this study may provide guidelines for designing unicondylar knee prostheses suitable for the Chinese population.