Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via SLC25A11-mediated depletion of mitochondrial glutathione.

BACKGROUND: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation. METHODS: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein. RESULTS: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation. CONCLUSION: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally.

The stability of functional brain network is maintained by homeostatic plasticity, which restores equilibrium following perturbation. As the initiation site of action potentials, the axon initial segment (AIS) of glutamatergic projection neurons (PyNs) undergoes dynamic adjustment that exerts powerful control over neuronal firing properties in response to changes in network states. Although AIS plasticity has been reported to be coupled with the changes of network activity, it is poorly understood whether it involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input to the AIS of cortical PyNs, specifically from chandelier cells (ChCs), are sufficient to drive homeostatic tuning of the AIS within 1-2 weeks, while those from parvalbumin-positive basket cells do not. This tuning is reflected in the morphology of the AIS, the expression level of voltage-gated sodium channels, and the intrinsic neuronal excitability of PyNs. Interestingly, the timing of AIS tuning in PyNs of the prefrontal cortex corresponds to the recovery of changes in social behavior caused by alterations of ChC synaptic transmission. Thus, homeostatic plasticity of the AIS at postsynaptic PyNs may counteract deficits elicited by imbalanced ChC presynaptic input. Teaser: Axon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.

Syringic acid suppresses ferroptosis of skeletal muscle cells to alleviate lower limb ischemia/reperfusion injury in mice via the HMGB1 pathway.

Ischemia/reperfusion (I/R) of skeletal muscle in the lower limbs is an important factor affecting the outcome of lower limbs ischemia patients, with no effective preventive or therapeutic approaches available. The study was to investigate the effect of syringic acid (SA) on I/R skeletal muscle in the lower limbs injury. Mice femoral artery I/R models and C2C12 cell hypoxia/reoxygenation (H/R) models was establish, tissue damage, inflammatory status, and high mobility group box 1 (HMGB1) pathway were evaluated using histological analysis, enzyme-linked immunosorbent assay, and western blotting. Further, the study detected the effect of SA on cell apoptosis, lipid peroxidation, Fe2+ level, and ferroptosis-related proteins expression. Finally, the effect of HMGB1 expression on SA in H/R stimulation was studied. SA alleviated pathological damage and reduced levels of IL-1ß, IL-6, and TNF-α in muscle tissues from femoral artery I/R mouse models. SA upregulated Bcl-2 and SOD as well as downregulated Bax, MDA, TBARS content, and Fe2+ level in H/R-induced cells. SA inhibited HMGB1 expression and promoted Nrf2, HO-1, GPX4, and SLC7A11 expressions in the injured tissues and cells. Such effects of SA on H/R-induced cells were rescued by HMGB1 overexpression. SA suppressed ferroptosis of skeletal muscle cells to alleviate lower limb I/R injury in mice by blocking the HMGB1 pathway, providing new insights for the treatment of lower limb ischemia-reperfusion injury.

LncRNA HOX transcript antisense RNA mitigates cardiac function injury in chronic heart failure via regulating microRNA-30a-5p to target KDM3A.

Long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been studied in multiple diseases, but the role of HOTAIR on chronic heart failure (CHF) through the regulation of microRNA (miR)-30a-5p and lysine-specific demethylase 3A (KDM3A) remains unexplored. This research aims to probe the effects of HOTAIR on CHF progression via modulating miR-30a-5p to target KDM3A. CHF mouse model was established by intraperitoneal injection of doxorubicin. The CHF mice were then injected with high-expressed HOTAIR, miR-30a-5p or KDM3A adenovirus vectors to determine the cardiac function, oxidative stress, inflammatory response, pathological change and cardiomyocyte apoptosis. HOTAIR, miR-30a-5p, KDM3A and Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) expression in CHF mice was detected. The binding relations among HOTAIR, miR-30a-5p and KDM3A were validated. HOTAIR and KDM3A were depleted, while miR-30a-5p was augmented in CHF mice. The elevated HOTAIR or KDM3A or could improve cardiac function, mitigate oxidative stress and pathological change, reduce inflammatory factor levels and cardiomyocyte apoptosis, while the increased miR-30a-5p exerted opposite effects. The miR-30a-5p elevation could reverse the effects of enriched HOTAIR, while BNIP3 reduction abrogated the effects of KDM3A on CHF. HOTAIR sponged miR-30a-5p that targeted KDM3A. HOTAIR improves cardiac injury in CHF via modulating miR-30a-5p to target KDM3A. This study provides novel therapeutic strategies for CHF treatment.

[Cortical 5-hydroxytryptamine receptor 3A (Htr3a) positive inhibitory neurons: diversity in type and function].

Cortical GABAergic inhibitory neurons are composed of three major classes, each expressing parvalbumin (PV), somatostatin (SOM) and 5-hydroxytryptamine receptor 3A (Htr3a), respectively. Htr3a+ inhibitory neurons are mainly derived from the caudal ganglionic eminence (CGE). This highly heterogeneous group of inhibitory neurons are comprised of many different subtypes with distinct molecular signatures, morphological and electrophysiological properties and connectivity patterns. In this review, we summarized recent research progress regarding cortical Htr3a+ inhibitory neurons, focusing on their molecular, morphological and electrophysiological diversity, and introduced some genetic mouse tools that were used to study Htr3a+ inhibitory neurons.

Topographical organization of mammillary neurogenesis and efferent projections in the mouse brain.

The mammillary body is a hypothalamic nucleus that has important functions in memory and spatial navigation, but its developmental principles remain not well understood. Here, we identify progenitor-specific Fezf2 expression in the developing mammillary body and develop an intersectional fate-mapping approach to demonstrate that Fezf2+ mammillary progenitors generate mammillary neurons in a rostral-dorsal-lateral to caudal-ventral-medial fashion. Axonal tracing from different temporal cohorts of labeled mammillary neurons reveal their topographical organization. Unsupervised hierarchical clustering based on intrinsic properties further identify two distinct neuronal clusters independent of birthdates in the medial nuclei. In addition, we generate Fezf2 knockout mice and observe the smaller mammillary body with largely normal anatomy and mildly affected cellular electrophysiology, in contrast to more severe deficits in neuronal differentiation and projection in many other brain regions. These results indicate that Fezf2 may function differently in the mammillary body. Our results provide important insights for mammillary development and connectivity.

Partial Cu ion exchange induced triangle hexagonal Mn0.45Cu0.05Cd0.5S nanocrystals for enhanced photocatalytic hydrogen evolution.

High crystallinity triangle hexagonal Mn0.45Cu0.05Cd0.5S was obtained by partial Cu ion exchange treatment on colloidal pristine Mn0.5Cd0.5S nanorods. The Mn0.45Cu0.05Cd0.5S nanotriangles exhibited a high hydrogen yield of 147 921 µmol g-1 h-1 under visible light irradiation, about 7.4 times higher than that of pristine Mn0.5Cd0.5S.

LncRNA-MIAT-Mediated miR-214-3p Silencing Is Responsible for IL-17 Production and Cardiac Fibrosis in Diabetic Cardiomyopathy.

As an important complication of diabetes mellitus, diabetic cardiomyopathy (DCM) is characterized by a silent development in its earlier stage and a deficient cardiomyocyte contractility in its late stage. So far, little advance has been achieved to reverse this pathological change. LncRNAs are defined as a large cluster of RNAs without the function of encoding proteins, but have the capacity in controlling gene expression. Interleukin-17 (IL-17), a proinflammatory cytokine, is a key regulator of host inflammation. Clinically, it plays a crucial role in the pathogenesis of cardiac interstitial fibrosis. In this study, we reported that high glucose-induced lncRNA-MIAT upregulation is responsible for proinflammatory IL-17 production in cardiomyocytes. The underlying mechanism is likely due to that lncRNA-MIAT specific attenuates miR-214-3p-mediated inhibitory effect on IL-17 expression. As a result, attenuated IL-17 expression significantly ameliorate cardiac fibrosis, followed by improvement of cardiac contractility. Taken together, our study first suggests that lncRNA-MIAT plays a key role in DCM and targeting lncRNA-MIAT may become a potential strategy to treat DCM.

Long Noncoding RNA XIST/miR-17/PTEN Axis Modulates the Proliferation and Apoptosis of Vascular Smooth Muscle Cells to Affect Stanford Type A Aortic Dissection.

Stanford type A aortic dissection (TAAD) is one of the most lethal cardiovascular diseases with an extremely high morbidity and mortality rate. LncRNA X-inactive specific transcript (XIST) is abundantly expressed in human thoracic aortic dissection, indicating it may play important roles in TAAD progression. However, the molecular mechanism of lncRNA XIST in TAAD is still in its infancy. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of XIST and miR-17 in the aortic wall tissues of TAAD patients and age-matched healthy volunteers. The relationships between XIST, miR-17, and PTEN were evaluated using dual-luciferase reporter, western blot, and qRT-PCR assays. The biological functions of XIST in rat aortic vascular smooth muscle cells (VSMCs) were explored with Cell Counting Kit 8 (CCK-8), qRT-PCR, and western blot assays. Results found that XIST was upregulated in aortic wall tissues of patients with TAAD and associated with the prognosis of patients with TAAD. Silence XIST facilitated VSMC proliferation and inhibited VSMC apoptosis, whereas restoration XIST displayed opposite effects. Moreover, mechanistic studies revealed that XIST contained binding sites for miR-17 and miR-17 downregulation reversed the elevation of cell proliferation and attenuation of cell apoptosis, which was induced by silence XIST. Further study revealed that XIST positively regulated PTEN expression through its competitive target miR-17. In conclusion, knockdown of lncRNA XIST might attenuate the progression of TAAD by sponging miR-17 and regulating the following downstream PTEN, which suggested a novel therapeutic target for TAAD treatment.

Viral approaches to study the mammalian brain: Lineage tracing, circuit dissection and therapeutic applications.

Viral vectors are widely used to study the development, function and pathology of neural circuits in the mammalian brain. Their flexible payloads with customizable choices of tool genes allow versatile applications ranging from lineage tracing, circuit mapping and functional interrogation, to translational and therapeutic applications. Different applications have distinct technological requirements, therefore, often utilize different types of virus. This review introduces the most commonly used viruses for these applications and some recent advances in improving the resolution and throughput of lineage tracing, the efficacy and selectivity of circuit tracing and the specificity of cell type targeting.