Baicalin alleviates angiotensin II-induced cardiomyocyte apoptosis and autophagy and modulates the AMPK/mTOR pathway.

As a main extraction compound from Scutellaria baicalensis Georgi, Baicalin exhibits various biological activities. However, the underlying mechanism of Baicalin on hypertension-induced heart injury remains unclear. In vivo, mice were infused with angiotensin II (Ang II; 500 ng/kg/min) or saline using osmotic pumps, followed by intragastrically administrated with Baicalin (5 mg/kg/day) for 4 weeks. In vitro, H9C2 cells were stimulated with Ang II (1 µM) and treated with Baicalin (12.5, 25 and 50 µM). Baicalin treatment significantly attenuated the decrease in left ventricular ejection fraction and left ventricular fractional shortening, increase in left ventricular mass, left ventricular systolic volume and left ventricular diastolic volume of Ang II infused mice. Moreover, Baicalin treatment reversed 314 differentially expressed transcripts in the cardiac tissues of Ang II infused mice, and enriched multiple enriched signalling pathways (including apoptosis, autophagy, AMPK/mTOR signalling pathway). Consistently, Baicalin treatment significantly alleviated Ang II-induced cell apoptosis in vivo and in vitro. Baicalin treatment reversed the up-regulation of Bax, cleaved-caspase 3, cleaved-caspase 9, and the down-regulation of Bcl-2. Meanwhile, Baicalin treatment alleviated Ang II-induced increase of autophagosomes, restored autophagic flux, and down-regulated LC3II, Beclin 1, as well as up-regulated SQSTM1/p62 expression. Furthermore, autophagy inhibitor 3-methyladenine treatment alleviated the increase of autophagosomes and the up-regulation of Beclin 1, LC3II, Bax, cleaved-caspase 3, cleaved-caspase 9, down-regulation of SQSTM1/p62 and Bcl-2 expression after Ang II treated, which similar to co-treatment with Baicalin. Baicalin treatment reduced the ratio of p-AMPK/AMPK, while increased the ratio of p-mTOR/mTOR. Baicalin alleviated Ang II-induced cardiomyocyte apoptosis and autophagy, which might be related to the inhibition of the AMPK/mTOR pathway.

Insights into the Peroxide-Bicyclic Intermediate Pathway of Aromatic Photooxidation: Experimental Yields and NOx-Dependency of Ring-Opening and Ring-Retaining Products.

Aromatic hydrocarbons are important contributors to the formation of ozone and secondary organic aerosols in urban environments. The different parallel pathways in aromatic oxidation, however, remain inadequately understood. Here, we investigated the production yields and chemical distributions of gas-phase tracer products during the photooxidation of alkylbenzenes at atmospheric OH levels with NOx present using high-resolution mass spectrometers. The peroxide-bicyclic intermediate pathway emerged as the major pathway in aromatic oxidation, accounting for 52.1 ± 12.6%, 66.1 ± 16.6%, and 81.4 ± 24.3% of the total OH oxidation of toluene, m-xylene, and 1,3,5-trimethylbenzene, respectively. Notably, the yields of bicyclic nitrates produced from the reactions of bicyclic peroxy radicals (BPRs) with NO were considerably lower (3-5 times) than what the current mechanism predicted. Alongside traditional ring-opening products formed through the bicyclic pathway (dicarbonyls and furanones), we identified a significant proportion of carbonyl olefinic acids generated via the 1,5-aldehydic H-shift occurring in subsequent reactions of BPRs + NO, contributing 4-7% of the carbon flow in aromatic oxidation. Moreover, the observed NOx-dependencies of ring-opening and ring-retaining product yields provide insights into the competitive nature of reactions involving BPRs with NO, HO2, and RO2, which determine the refined product distributions and offer an explanation for the discrepancies between the experimental and model-based results.

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization.

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models. Methods: We developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356 - 385) against NMDARs in 3-week-old female C57BL/6J mice. Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed. Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

[Identification of ecological functional zoning and its influencing factors in the Sihu Lake Basin, China]. / å››æ¹–æµåŸŸç”Ÿæ€åŠŸèƒ½åˆ†åŒºåŠå ¶å½±å“å› ç´ è¯†åˆ«.

Rational delineation of ecological functional areas and clarification of their driving factors are of significance for maintaining regional ecosystem stability. We assessed six ecosystem services of Sihu Lake Basin located in Jianghan Plain using InVEST and RUSLE models and recreational scoring methods. By using K-means clustering, we identified the ecosystem service bundles, and delineated the ecological functional areas in combination with ecological sensitivity and ecosystem service bundles. The dominant driving factors of different ecological functional areas were analyzed by Geodetector. The results showed that the spatial distributions of habitat quality and carbon sequestration services were similar, with high values being mainly concentrated in Changhu Lake Basin and Honghu Lake Basin. However, the spatial distributions of crop production and soil conservation services were different, with high-value areas concentrated in the northwest area with mountains. The high values of water production service were mainly concentrated in the eastern part of Honghu Lake Basin, while the high-value areas of ecological recreation service were mainly concentrated in the northwest area and the southern part of Honghu Lake Basin. The Sihu Lake Basin could be classified into crop production bundle, habitat quality bundle, and urban living bundle according to cluster analysis. The low ecological sensitivity areas accounted for 59.0% of the Sihu Lake Basin. We classified the study area into ecological restoration areas, ecological conservation areas, ecological transition areas, ecological development areas, and comprehensive use areas by combination of ecological sensitivity and ecosystem service bundles. The geodetector results indicated that the driving factors of each ecological function zone were significantly different. The natural factors significantly influenced the ecological restoration zone, while the normalized vegetation index and population density were the main influencing factors in the ecological conservation zone and the ecological development zone, respectively. Land use type was the main influencing factor in the ecological transition zone and the comprehensive use zone. The results could provide important support for coordinated regional social development and environmental protection.

Neferine ameliorates hypertensive vascular remodeling modulating multiple signaling pathways in spontaneously hypertensive rats.

BACKGROUND: Neferine exhibits therapeutic effects on anti-hypertension. However, the effect of neferine on hypertensive vascular remodeling remains unexplored. Therefore, the current study was to investigate the effect of neferine on hypertensive vascular remodeling and its underlying mechanisms. METHODS: Total 30 male spontaneously hypertensive rats (SHRs) were divided randomly into five groups, including SHR, Neferine-L (2.5 mg/kg/day), Neferine-M (5 mg/kg/day), Neferine-H (10 mg/kg/day), and Valsartan (10 mg/kg/day) groups (n = 6 for each group). Wistar Kyoto (WKY) rats were set as control group (n = 6). Noninvasive blood pressure system, ultrasound, hematoxylin and eosin staining, masson trichrome staining were used to detect the blood pressure, pulse wave velocity (PWV), pathological changes and collagen content in abdominal aortas of SHRs. RNA-sequencing and immunohistochemistry(IHC) analyses were used to identify and verify the differentially expressed transcripts and activation of associated signaling pathways in SHRs. RESULTS: Various concentrations of neferine or valsartan treatment substantially reduced the elevation of blood pressure, PWV, and abdominal aortic thickening of SHRs. RNA-sequencing and KEGG analyses recognized 441 differentially expressed transcripts and several enriched pathways (including PI3K/AKT and TGF-ß/Smad2/3 signaling pathways) after neferine treatment. Masson trichromatic staining and IHC analysis demonstrated that neferine treatment decreased the collagen content and down-regulated the protein expression of PCNA, collagen I & III, and fibronectin, as well as p-PI3K, p-AKT, TGF-ß1 and p-Smad2/3 in abdominal aortic tissues of SHRs. CONCLUSION: Neferine treatment exhibits therapeutic effects on anti-hypertension and reduces vascular remodeling, as well as suppresses the abnormal activation of multiple signaling pathways, including PI3K/AKT and TGF-ß1/Smad2/3 pathways.

Research Progress of Grassland Ecosystem Structure and Stability and Inspiration for Improving Its Service Capacity in the Karst Desertification Control.

The structure and stability of grassland ecosystems have a significant impact on biodiversity, material cycling and productivity for ecosystem services. However, the issue of the structure and stability of grassland ecosystems has not been systematically reviewed. Based on the Web of Science (WOS) and China National Knowledge Infrastructure (CNKI) databases, we used the systematic-review method and screened 133 papers to describe and analyze the frontiers of research into the structure and stability of grassland ecosystems. The research results showed that: (1) The number of articles about the structure and stability of grassland ecosystems is gradually increasing, and the research themes are becoming increasingly diverse. (2) There is a high degree of consistency between the study area and the spatial distribution of grassland. (3) Based on the changes in ecosystem patterns and their interrelationships with ecosystem processes, we reviewed the research progress and landmark results on the structure, stability, structure-stability relationship and their influencing factors of grassland ecosystems; among them, the study of structure is the main research focus (51.12%), followed by the study of the influencing factors of structure and stability (37.57%). (4) Key scientific questions on structural optimization, stability enhancement and harmonizing the relationship between structure and stability are explored. (5) Based on the background of karst desertification control (KDC) and its geographical characteristics, three insights are proposed to optimize the spatial allocation, enhance the stability of grassland for rocky desertification control and coordinate the regulation mechanism of grassland structure and stability. This study provided some references for grassland managers and relevant policy makers to optimize the structure and enhance the stability of grassland ecosystems. It also provided important insights to enhance the service capacity of grassland ecosystems in KDC.

A neural circuit from the dorsal CA3 to the dorsomedial hypothalamus mediates balance between risk exploration and defense.

An appropriate balance between explorative and defensive behavior is essential for the survival and reproduction of prey animals in risky environments. However, the neural circuit and mechanism that allow for such a balance remains poorly understood. Here, we use a semi-naturalistic predator threat test (PTT) to observe and quantify the defense-exploration balance, especially risk exploration behavior in mice. During the PTT, the activity of the putative dorsal CA3 glutamatergic neurons (dCA3Glu) is suppressed by predatory threat and risk exploration, whereas the neurons are activated during contextual exploration. Moreover, optogenetic excitation of these neurons induces a significant increase in risk exploration. A circuit, comprising the dorsal CA3, dorsal lateral septal, and dorsomedial hypothalamic (dCA3Glu-dLSGABA-DMH) areas, may be involved. Moreover, activation of the dCA3Glu-dLSGABA-DMH circuit promotes the switch from defense to risk exploration and suppresses threat-induced increase in arousal.

Effect of Cultivated Pastures on Soil Bacterial Communities in the Karst Rocky Desertification Area.

Soil bacteria play an important role in regulating the process of vegetation restoration in karst ecosystems. However, the effects of vegetation restoration for different cultivated pastures on soil bacterial communities in the karst rocky desertification regions remain unclear. Therefore, we hypothesized that mixed pasture is the most effective for soil bacterial communities among different vegetation restorations. In this study, we systematically studied the soil properties and soil bacterial communities in four vegetation restoration modes [i.e., Dactylis glomerata pasture (DG), Lolium perenne pasture (LP), Lolium perenne + Trifolium repens mixed pasture (LT), and natural grassland (NG)] by using 16S rDNA Illumina sequencing, combined with six soil indicators and data models. We found that the vegetation restoration of cultivated pastures can improve the soil nutrient content compared with the natural grassland, especially LT treatment. LT treatment significantly increased the MBC content and Shannon index. The vegetation restoration of cultivated pastures significantly increased the relative abundance of Proteobacteria, but LT treatment significantly decreased the relative abundance of Acidobacteria. Soil pH and MBC significantly correlated with the alpha diversity of soil bacterial. Soil pH and SOC were the main factors that can affect the soil bacterial community. FAPROTAX analysis showed LT treatment significantly decreased the relative abundance of aerobic chemoheterotrophs. The results showed that the bacterial communities were highly beneficial to soil restoration in the LT treatment, and it confirmed our hypothesis. This finding provides a scientific reference for the restoration of degraded ecosystems in karst rocky desertification areas.

Dysfunction of the Hippocampal-Lateral Septal Circuit Impairs Risk Assessment in Epileptic Mice.

Temporal lobe epilepsy, a chronic disease of the brain characterized by degeneration of the hippocampus, has impaired risk assessment. Risk assessment is vital for survival in complex environments with potential threats. However, the underlying mechanisms remain largely unknown. The intricate balance of gene regulation and expression across different brain regions is related to the structure and function of specific neuron subtypes. In particular, excitation/inhibition imbalance caused by hyperexcitability of glutamatergic neurons and/or dysfunction of GABAergic neurons, have been implicated in epilepsy. First, we estimated the risk assessment (RA) by evaluating the behavior of mice in the center of the elevated plus maze, and found that the kainic acid-induced temporal lobe epilepsy mice were specifically impaired their RA. This experiment evaluated approach-RA, with a forthcoming approach to the open arm, and avoid-RA, with forthcoming avoidance of the open arm. Next, results from free-moving electrophysiological recordings showed that in the hippocampus, ∼7% of putative glutamatergic neurons and ∼15% of putative GABAergic neurons were preferentially responsive to either approach-risk assessment or avoid-risk assessment, respectively. In addition, ∼12% and ∼8% of dorsal lateral septum GABAergic neurons were preferentially responsive to approach-risk assessment and avoid-risk assessment, respectively. Notably, during the impaired approach-risk assessment, the favorably activated dorsal dentate gyrus and CA3 glutamatergic neurons increased (∼9%) and dorsal dentate gyrus and CA3 GABAergic neurons decreased (∼7%) in the temporal lobe epilepsy mice. Then, we used RNA sequencing and immunohistochemical staining to investigate which subtype of GABAergic neuron loss may contribute to excitation/inhibition imbalance. The results show that temporal lobe epilepsy mice exhibit significant neuronal loss and reorganization of neural networks. In particular, the dorsal dentate gyrus and CA3 somatostatin-positive neurons and dorsal lateral septum cholecystokinin-positive neurons are selectively vulnerable to damage after temporal lobe epilepsy. Optogenetic activation of the hippocampal glutamatergic neurons or chemogenetic inhibition of the hippocampal somatostatin neurons directly disrupts RA, suggesting that an excitation/inhibition imbalance in the dHPC dorsal lateral septum circuit results in the impairment of RA behavior. Taken together, this study provides insight into epilepsy and its comorbidity at different levels, including molecular, cell, neural circuit, and behavior, which are expected to decrease injury and premature mortality in patients with epilepsy.

Research Advancement in Grassland Ecosystem Vulnerability and Ecological Resilience and Its Inspiration for Improving Grassland Ecosystem Services in the Karst Desertification Control.

Karst desertification control of grasslands balances the ecological and economic benefits of ecological restoration and rural ecological animal husbandry development. In the context of global changes and intensified human activities, the fragility of grassland ecosystems under karst desertification control is becoming increasingly evident, and enhancing the ecological resilience and ecosystem services of grasslands is an issue that urgently needs to be addressed. In this paper, the CNKI literature, WOS core databases and Goolgle scholar were used as search sources, identifying 179 articles related to the study of grassland ecosystem vulnerability and ecological resilience. This research systematically reviewed the progress of grassland ecosystem vulnerability research and analyzed the relationship between grassland ecosystem services (GESs) and grassland ecosystem vulnerability and resilience. The direction of enhancing GESs in karst areas is indicated in terms of the reciprocal feedback, synergistic relationship, and mechanism of action of GESs, vulnerability, and resilience. It is also emphasized that the karst desertification area should provide an ecological foundation for the sustainable development of the regional environment around the supply-and-demand relationship of GESs, the trade-off synergy of service flow, and the enhancement of ecological resilience, thereby consolidating the effectiveness of karst desertification control, enhancing GESs, and helping rural revitalization.

Effects of Landscape Type Change on Spatial and Temporal Evolution of Ecological Assets in a Karst Plateau-Mountain Area.

The rocky desertification control project in karst areas exacerbates the transfer of landscape types, changes the ecosystem structure and function, and has a significant impact on ecological assets. How to analyze the relationship between landscape type shifts and the spatial and temporal evolution of ecological assets is one of the key questions that need to be addressed to achieve the goal of overall improvement in ecosystem quality and sustainable regional economic development. This study takes Qixingguan District, Bijie City, Guizhou Province-a typical karst plateau mountainous area-as the research object, and analyzes the spatial and temporal evolution characteristics of landscape type shifts and ecological assets triggered by rock desertification management from 1995-2018, based on the equivalence factor method, combined with the contribution rate, spatial autocorrelation, and sensitivity research methods. The results showed that arable land, grassland, and woodland were the main landscape types in the study area. The value of ecological assets showed a trend of increasing and then decreasing, with an overall increase of 87.70 × 106 yuan. The distribution pattern of ecological asset value from southwest to northeast is "high-low-high". There is a significant positive correlation in the spatial distribution of the overall ecological assets, with similar aggregation between neighboring units. The expansion of forest land was the main factor for the rapid increase of assets from 1995 to 2010, with a contribution of 98.12%; the conversion of arable land and grassland to construction land was the main factor for the decrease of assets from 2010 to 2018, with a percentage of 81.06%, where the value of each type of service was mainly composed of five items, such as soil formation and conservation, biodiversity conservation and gas regulation, water conservation, and climate regulation. This study shows that spatial and temporal evolution assessment of ecological assets is an important manifestation of the effectiveness of rocky desertification control, which can provide decision support to resource managers and users for regional ecological environment construction.

Research on accounting and detection of volatile organic compounds from a typical petroleum refinery in Hebei, North China.

A volatile organic compound (VOC) emissions inventory of the petroleum refinery in Hebei was established. This refinery emits 1859.2 tons of VOCs per year, with wastewater collection and treatment system being the largest emissions source, accounting for 59.6% individually, followed by the recirculating cooling water system (13.4%), storage tanks (11.1%), and equipment leaks (9.4%). Organized and fugitive samples were collected simultaneously for different processes of each emissions source. A total of 100 VOC species were characterized and quantified using a gas chromatography-mass spectrometry/flame ionization detection system. The VOC emissions concentrations and chemical composition of each process were quite different. Most of the processes used alkanes as the main chemome. We concluded from the composite source profile weighted by the amount of VOC emissions that the characteristic species of this petroleum refinery were ethane (15.4%), propylene (11.7%), propane (8.5%), iso-pentane (8.3%), and toluene (4.7%). The ozone (O3) formation potential (OFP) and secondary organic aerosol formation potential (SOAP) were evaluated, and the results indicated that alkenes (mainly propylene) and aromatics (mainly toluene) were the priority control compounds. This study clarifies the current status of VOC emissions in the refinery in terms of emissions intensity, emissions components, and O3 and SOA reactivity. The key emissions sources and species screened provide scientific support for reducing refined emissions from the petrochemical industry.

Development, performance evaluation, and clinical application of a Rapid SARS-CoV-2 IgM and IgG Test Kit based on automated fluorescence immunoassay.

The ongoing coronavirus disease 2019 (COVID-19) epidemic has made a huge impact on health, economies, and societies all over the world. Although reverse transcription-polymerase chain reaction (RT-PCR)-based nucleic acid detection has been primarily used in the diagnosis of COVID-19, it is time-consuming with limited application scenarios and must be operated by qualified personnel. Antibody test, particularly point-of-care antibody testing, is a suitable complement to nucleic acid test as it provides rapid, portable, and cost-effective detection of infections. In this study, a Rapid Antibody Test Kit was developed based on fluorescence immunochromatography for the sensitive, accurate, and automated detection of immunoglobulin M (IgM) and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human serum, plasma, and whole blood samples within 10 min. The sensitivity, specificity, precision, and stability of the test kit were of good performance. No cross-activity and no interference was observed. In the multiple-center parallel study, 223 samples from hospitalized patients were used to evaluate the clinical specificity of the test. Both SARS-CoV-2 IgM and IgG achieved a clinical specificity of 98.21%. The clinical sensitivities of SARS-CoV-2 IgM and IgG were 79.54% and 87.45%, respectively, among 733 reverse transcription-polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 samples. For the combined IgM and IgG assays, the sensitivity and specificity were 89.22% and 96.86%, respectively. Our results demonstrate that the combined use of IgM and IgG could serve as a more suitable alternative detection method for patients with COVID-19, and the developed kit is of great public health significance for the prevention and control of the COVID-19 pandemic.

Detection of circulating genetically abnormal cells in peripheral blood for early diagnosis of non-small cell lung cancer.

BACKGROUND: Circulating genetically abnormal cells (CACs) with specific chromosome variations have been confirmed to be present in non-small cell lung cancer (NSCLC). However, the diagnostic performance of CAC detection remains unclear. This study aimed to evaluate the potential clinical application of the CAC test for the early diagnosis of NSCLC. METHODS: In this prospective study, a total of 339 participants (261 lung cancer patients and 78 healthy volunteers) were enrolled. An antigen-independent fluorescence in situ hybridization was used to enumerate the number of CACs in peripheral blood. RESULTS: Patients with early-stage NSCLC were found to have a significantly higher number of CACs than those of healthy participants (1.34 vs. 0.19; P < 0.001). The CAC test displayed an area under the receiver operating characteristic (ROC) curve of 0.76139 for discriminating stage I NSCLC from healthy participants with 67.2% sensitivity and 80.8% specificity, respectively. Compared with serum tumor markers, the sensitivity of CAC assays for distinguishing early-stage NSCLC was higher (67.2% vs. 48.7%, P < 0.001), especially in NSCLC patients with small nodules (65.4% vs. 36.5%, P = 0.003) and ground-glass nodules (pure GGNs: 66.7% vs. 40.9%, P = 0.003; mixed GGNs: 73.0% vs. 43.2%, P < 0.001). CONCLUSIONS: CAC detection in early stage NSCLC was feasible. Our study showed that CACs could be used as a promising noninvasive biomarker for the early diagnosis of NSCLC. KEY POINTS: What this study adds: This study aimed to evaluate the potential clinical application of the CAC test for the early diagnosis of NSCLC. Significant findings of the study: CAC detection in early stage NSCLC was feasible. Our study showed that CACs could be used as a promising noninvasive biomarker for the early diagnosis of NSCLC.

Cell sensing and decision-making in confinement: The role of TRPM7 in a tug of war between hydraulic pressure and cross-sectional area.

How cells sense hydraulic pressure and make directional choices in confinement remains elusive. Using trifurcating Ψ-like microchannels of different hydraulic resistances and cross-sectional areas, we discovered that the TRPM7 ion channel is the critical mechanosensor, which directs decision-making of blebbing cells toward channels of lower hydraulic resistance irrespective of their cross-sectional areas. Hydraulic pressure-mediated TRPM7 activation triggers calcium influx and supports a thicker cortical actin meshwork containing an elevated density of myosin-IIA. Cortical actomyosin shields cells against external forces and preferentially directs cell entrance in low resistance channels. Inhibition of TRPM7 function or actomyosin contractility renders cells unable to sense different resistances and alters the decision-making pattern to cross-sectional area-based partition. Cell distribution in microchannels is captured by a mathematical model based on the maximum entropy principle using cortical actin as a key variable. This study demonstrates the unique role of TRPM7 in controlling decision-making and navigating migration in complex microenvironments.

IRGM1 regulates oxidized LDL uptake by macrophage via actin-dependent receptor internalization during atherosclerosis.

Macrophage derived foam cells are actively involved in the initial phase of atherosclerosis. Uptake of modified lipoprotein such as oxidized LDL (oxLDL) is a critical step for foam cell formation. CD36 is the major receptor mediating oxLDL uptake by macrophage. However, the molecular mechanism underlying CD36 mediated oxLDL uptake remains unclear. Here we reported that IRGM1 (IRGM in human), a member of immunity-related small GTPase family, is essential for the actin-dependent CD36 mediated oxLDL uptake by macrophage. IRGM/IRGM1 was highly expressed by macrophage around the atherosclerotic plaque and was up-regulated by oxLDL both in vitro and in vivo. Moreover loss of IRGM/IRMG1 significantly decreased oxLDL uptake in both mouse and human. Furthermore, the IRGM1 knock-out mice displayed impaired CD36 internalization in macrophage, which was associated with the deficiency of F-actin polymerization. These results revealed a novel function of IRGM1 in regulating oxLDL uptake by macrophage during atherosclerosis.

Immune-related GTPase Irgm1 exacerbates experimental auto-immune encephalomyelitis by promoting the disruption of blood-brain barrier and blood-cerebrospinal fluid barrier.

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a T cell-mediated autoimmune condition characterized by prominent inflammation in the CNS. In this model, autoreactive T cells are primed in peripheral lymph nodes and migrate into uninflamed CNS across blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB) to initiate inflammation. However, the molecular mechanism controlling T cell migration remains to be determined. In an in vivo EAE mouse model, we have shown that Irgm1 (also known as LRG-47), a member of the immunity-related GTPase family, promotes the disruption of both BCSFB and BBB, and exacerbates the phenotypes of MOG-induced EAE. During EAE, Irgm1 was up-regulated in reactive astrocytes, ependymal cells and epithelial cells of the choroids plexus, which, in turn, promotes T cell infiltration into the CNS. Electron microscopy study showed that the MOG-induced disruption of both BBB and BCSFB was protected in the Irgm1(-/-) mice. Moreover, the expression of Claudin-5 (CLN-5), a major molecular determinant of BBB, in brain microvessel endothelial cells (BMVECs) was decreased in WT EAE mice while increased in Irgm1(-/-) mice. In addition, the expression of CC-chemokine ligand 20 (CCL-20), an important chemokine mediating lymphocyte trafficking across BCSFB, in the epithelial cells of choroids plexus was significantly suppressed in naïve and EAE-induced Irgm1(-/-) mice. These data suggest that Irgm1 is an important molecular regulator for the properties of both BBB and BCSFB, and a proinflammatory factor for EAE.

Immune-related GTPase M (IRGM1) regulates neuronal autophagy in a mouse model of stroke.

Autophagy is an important cellular recycling mechanism through self-digestion in responses to cellular stress such as starvation. Studies have shown that autophagy is involved in maintaining the homeostasis of the neural system during stroke. However, molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. Previously, we and others have shown that immune-related GTPase M (IRGM; termed IRGM1 in the mouse nomenclature) can regulate the survival of immune cells through autophagy in response to infections and autoimmune conditions. Here, using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we found that IRGM1 was upregulated in the ischemic side of the brain, which was accompanied by a significant autophagic response. In contrast, neuronal autophagy was almost complete lost in Irgm1 knockout (KO) mice after pMCAO induction. In addition, the infarct volume in the Irgm1-KO pMCAO mice was significantly increased as compared to wild-type mice. Histological studies suggested that, at the early stage (within 24 h) of ischemia, the IRGM1-dependent autophagic response is associated with a protection of neurons from necrosis in the ischemic core but a promotion of neuronal apoptosis in the penumbra area. These data demonstrate a novel role of IRGM1 in regulating neuronal autophagy and survival during ischemic stroke.